The 40 years since the seminal papers of Hodgkin and Huxley appeared have been extraordinarily productive in terms of understanding the molecular basis for electrical activity. The Hodgkin-Huxley proposal that electrical excitability should be understood in terms of voltage-dependent changes in discrete sites has been resoundingly verified. Indeed, the Hodgkin-Huxley framework is remarkable in that its essential elements have remained largely intact as molecular understanding has advanced. This robustness is, at least in part, a result of the fact that Hodgkin and Huxley developed a mathematical model, based on simple physical arguments, that was sufficiently comprehensive to describe the kinetics of the voltage-clamped currents and yet simple enough to be predictive. The predictive features were demonstrated early by the reconstruction of both space-clamped and propagated action potentials on a desk-top calculator (293) and, later, when the sites of Hodgkin and Huxley developed into being well-characterized molecular structures. Voltage- and ligand-dependent ion-selective channels are now the established framework within which cellular electrophysiology is being pursued. Moreover, electrophysiological measurements of membrane and single-channel currents have become essential tools to examine molecular questions pertaining to channel structure and activity. The last 10 years have witnessed spectacular activity, which has resulted from two developments, the giga-seal patch clamp (249) and the elucidation of primary sequences of a number of channel-forming proteins (494), along with the first outlines of their low-resolution three-dimensional structures (651). The stage is now set for 1) applying a variety of convergent techniques to decipher molecular structural details at high resolution, and 2) seeking to understand the complex dynamic functions, gating, and ion selectivity at the molecular level. The early successes are likely to be in understanding the molecular determinants of ion conductance and selectivity, initially in terms of quantitative descriptions of how a sequence modification can alter a channel's permeability characteristics. Channel gating is a far more elusive target because it involves molecular rearrangements, which are poorly understood at any level of description and which may be modified by the channel's environment. The general mechanisms of ion permeation and gating will differ among different classes of ion channels, but a molecular understanding of either phenomenon must eventually be based on an understanding of intermolecular forces, which are invariant among all channel types.(ABSTRACT TRUNCATED AT 400 WORDS)