Signal transduction originates at the membrane, where the clustering of signaling proteins is a key step in transmitting a message. Membranes are difficult to study, and their influence on signaling is still only understood at the most rudimentary level. Recent advances in the biophysics of membranes, surveyed in this review, have highlighted a variety of phenomena that are likely to influence signaling activity, such as local composition heterogeneities and long-range mechanical effects. We discuss recent mechanistic insights into three signaling systems—Ras activation, Ephrin signaling and the control of actin nucleation—where the active role of membrane components is now appreciated and for which experimentation on the membrane is required for further understanding.