1. The human ether à-go-go-related gene (HERG) encodes a K+ channel that is believed to be the basis of the delayed rectified current, IKr, in cardiac muscle. We studied HERG expressed in Xenopus oocytes using a two-electrode and cut-open oocyte clamp technique with [K+]0 of 2 and 98 mM. 2. The time course of activation of the channel was measured using an envelope of tails protocol and demonstrated that activation of the heterologously expressed HERG current (IHERG) was sigmoidal in onset. At least three closed states were required to reproduce the sigmoid time course. 3. The voltage dependence of the activation process and its saturation at positive voltages suggested the existence of at least one relatively voltage-insensitive step. A three closed state activation model with a single voltage-insensitive intermediate closed state was able to reproduce the time and voltage dependence of activation, deactivation and steady-state activation. Activation was insensitive to changes in [K+]0. 4. Both inactivation and recovery time constants increased with a change of [K+]0 from 2 to 98 mM. Steady-state inactivation shifted by approximately 30 mV in the depolarized direction with a change from 2 to 98 mM K+0. 5. Simulations showed that modulation of inactivation is a minimal component of the increase of this current by [K+]0, and that a large increase in total conductance must also occur.