Our January 2025 issue caps two decades of Nature Chemical Biology publishing major advances across the breadth of chemical biology. This issue is the 236th produced — a milestone that would not have happened without all the contributions and support from the chemical biology community, and the dedication of all the editors who have served on the journal editorial team over the past 20 years.

The journal was first launched in 2005 by the founding chief editor Terry L. Sheppard, with the aim of providing a forum to promote the publication of high-impact research at the interface of biology and chemistry, which was outlined in the opening editorial1. Two decades later, this remains the core mission of the journal. Over the years, it has been an honor and a privilege to observe the many innovations within the chemical biology community with the development of new methods and chemical tools, the application of which has unleashed a myriad of new biological insights.

In this special issue, we have chosen to celebrate several landmark achievements that have shaped the field with a set of retrospective News & Views pieces. Although the selection of topics was subjective and far from comprehensive, these pieces discuss the lasting legacy of some major findings and how they continue to influence chemical biology research to this day. Strain-promoted azide–alkyne cycloaddition under physiological conditions was reported by Carolyn Bertozzi’s group in the Journal of the American Chemical Society in 2004. This advance was made shortly before Nature Chemical Biology launched but it was a key innovation in bio-orthogonal chemistry that provided a route to selectively modify biomolecules in cells with limited toxicity and has facilitated numerous studies over the past 20 years. Kenward Vong and Katsunori Tanaka discuss this work and the applications this reaction has enabled in the intervening years.

Andreas Gloger and Jörg Scheuermann look back at a 2009 Nature Chemical Biology work by scientists of Praecis Pharmaceutics/GSK in which they developed and screened the first large-member DNA-encoded library, while Xu-Dong Kong and Changlin Tian discuss another 2009 Nature Chemical Biology publication from Christian Heinis, Greg Winter and colleagues in which they constructed a phage-encoded bicyclic peptide library that used a chemical linker for cyclization; both types of library continue to be used to this day.

Marcus Conrad and Adam Wahida reflect on a 2012 study in Cell by Brent Stockwell’s group that first termed the process of iron and lipid peroxidation-mediated cell death as ferroptosis. They also discuss the many new molecular and cellular players identified since that time. Mary E. Matyskiela discusses two papers from 2015, one in Science by a team led by Jay Bradner and another in Nature Chemical Biology from Craig Crews’s group, that introduced the viability of heterobifunctional degraders or PROTACs for cellular and in vivo applications. Brian Liau and colleagues re-examine the development of a base editor (reported by David Liu’s group in Nature in 2016) that achieved precise genome editing at single-base resolution. This not only enhanced the promise of CRISPR-based therapeutics but also expanded the range of tools for basic research studies.

Kridsadakorn Prakinee and Pimchai Chaiyen re-examine a 2016 report in Science from Frances Arnold’s group that showcased the power of directed evolution to attain biocatalysts capable of new-to-nature chemistry and discuss how this approach has subsequently been utilized for other biocatalyst applications. Finally, Charlotte M. Deane and colleagues look back on the seminal report of AlphaFold2 in Nature and the impact this and its subsequent advanced versions have had on structural biology in predicting protein complexes.

While developments in areas such as signal transduction, small-molecule inhibitors and biosynthesis have remained a consistent feature in our issues, it is clear that the advancement of chemical biology research has been both reflective and responsive to the changing world landscape. Perhaps the clearest example was during the COVID-19 pandemic, which stimulated intense characterization of the virus and work on lipid nanoparticles for delivering mRNA-based vaccines. Over the past 20 years there have, however, been many other foundational advancements, such as improvements in cryo-electron microscopy resolution and the adoption of AlphaFold2 structural modeling. In addition, the rise of artificial intelligence and machine learning approaches2 along with CRISPR gene editing has impacted many fields, including speeding up the process of small-molecule discovery and opening new routes to potential therapeutics3. Other innovations in synthetic biology and metabolic engineering have benefited greatly from progress in sequencing technologies and along the way new topics such as phase separation and the role of biomolecular condensates4 have come to the fore.

While we acknowledge the substantial progress chemical biology research has made over the years, there is always more work that needs to be done. To highlight some of the most important challenges still facing this field, we have included a Q&A piece ‘Reflecting on 20 years of progress’ with three experts (Sarah E. O’Connor, Benjamin F. Cravatt and Chengqi Yi) reflecting on the major changes in both their own research and on the broader chemical biology landscape. One consistent theme that emerged was the importance of improved nucleic acid sequencing and transcriptomics technology along with innovations in covalent and bio-orthogonal chemistry that has facilitated much of their research.

We have also asked a diverse group of chemical biologists: “What do you think are the most exciting frontiers or the most needed developments in your main field of research?” Their comments, which are in the ‘Thoughts for the future’ piece, offer an overview of some of the current challenges the field faces, along with some potential solutions to address them. We hope that these comments will inspire the community to tackle these challenges with the aim of advancing the field and we look forward to seeing the progress in the years ahead.

The journal has introduced many changes over the years in an effort to improve how we serve our authors and readership. We stopped publishing new research as Letters in 2007, and the last Brief Communication was published in March 2020. Now all original research is published as an Article and there is no distinction based on article length or perceived timeliness. We have also changed how we deal with comment and opinion pieces over the years and introduced Matters Arising to provide a better avenue for post-publication commentary on Articles. Upon reflection, we hope that we have successfully fulfilled the journal’s initial mission statement in providing a high-visibility forum for the publication of top-tier original research and commentary for the chemical biology community. We continue to be impressed with the constant innovation and new insights that are revealed with each publication and look forward to seeing what the next 20 years will bring.