Congestive heart failure claims more lives than any other disease in the Western world and is caused by impaired heart contractility. In recent years it has become apparent that defective regulation of calcium cycling in heart muscle cells has a pivotal role in heart contractility. In this issue, Marks and colleagues review the molecular basis of calcium cycling and propose novel therapeutic approaches to reverse these defects. For a small number of people with serious heart failure, a transplant is sometimes the only option, and with it comes a regimen of non-specific immunosuppressive drugs and their unwanted side effects. O'Shea and colleagues describe how the JAK/STAT pathway is emerging as a potential target for immunosuppressive therapy, and in particular discuss excellent prospects for the selectively expressed JAK3. Hopefully, non-specific cancer treatments could soon be surpassed by novel targeted therapies, such as those approved for non-small-cell lung cancer, discussed this month in 'From the Analyst's Couch', and cetuximab for colorectal cancer, profiled in 'Fresh from the Pipeline'. Selectivity is also still an issue for arguably the most successful class of drug targets — the G-protein-coupled receptors. The ongoing discovery and deorphanization of GPCRs suggests that they will continue to be attractive drug targets, but many challenges for the field remain. In the second instalment of our 'Twenty Questions' series, we asked twenty academic experts in GPCR research to give us their thoughts on the status of the field today. Their answers provide a fascinating insight into the complexities of GPCR pharmacology and show that although there has been progress, there is still much to learn and new tools to develop. We hope that this section will serve as a valuable knowledge base from which to move forward.