The dihydropyridine series of drugs contains both potent antagonists and potent activators of Ca2+ channels. The structural differences between antagonists and activators are small and, indeed, activators can behave as antagonists at high levels of membrane depolarization. Here, David Triggle and David Rampe describe recent insights into the factors--including structure of the drug and activation state of the channel--that influence the behavior of these drugs, and discuss models that have been proposed to describe their mechanism of action.