Traditionally, signalling through seven-transmembrane receptors (7TMRs) — which are one of the largest classes of drug targets — was thought to be mediated solely via G proteins. Recently, however, it has been increasingly appreciated that β-arrestins, which mediate receptor desensitization, can also initiate their own functionally distinct signalling pathways. In the first review this month, Lefkowitz and colleagues describe recent advances in the characterization of β-arrestin-mediated signalling at 7TMRs, and consider the implications for drug discovery. Another review also highlights the therapeutic significance of emerging knowledge of cell signalling pathways: those mediated through the activation of store-operated calcium release-activated calcium (CRAC) channels. Parekh summarizes the gating and function of CRAC channels, and considers both their potential as therapeutic targets — in particular, in immuno-inflammatory diseases — and the development of channel blockers. Both perspective articles this month discuss approaches that may contribute to reducing attrition rates in drug development. Genomic knowledge is revealing potential biomarkers in oncology that could be used to improve success in clinical trials by targeting treatments to patients who are more likely to respond. In the first article, Schilsky focuses on the opportunities and challenges in developing anticancer drugs in biomarker-defined populations, emphasizing the need for more personalized therapy. Second, Ebert and Svendsen discuss the potential of using embryonic or induced pluripotent stem cells to improve drug screening, and also to model diseases such as neurodegenerative disorders. Finally, Citron reviews the development of disease-modifying therapies for the most common neurodegenerative disorder, Alzheimer's disease, highlighting approaches, such as those that target amyloid-β, for which clinical data could soon clarify their true potential.