Numerous drugs have been invented to counteract heart failure, but some have not lived up to their initial promise. As David Kass explains, the development of drugs to increase cardiac contractility has been particularly frustrating—but failure is also leading to new biological insights and new experimental approaches. Mark Anderson and Peter Mohler explore new ways of targeting calcium-mediated signaling in the heart—with a focus on combating heart failure by targeting 'local' forms of signaling in heart muscle.