The term ischemic penumbra, originally applied to brain tissue perfused at values between the functional and morphologic thresholds, has recently been extended to characterize ischemically affected but still viable tissue with uncertain chances for infarction or recovery. Results have accumulated supporting the concept of the ischemic penumbra as a dynamic process of impaired perfusion and metabolism eventually propagating with time from the center of ischemia to the neighboring tissue. As mediators and modulators of this process, waves of depolarization, extracellular increases in excitatory amino acids, activation of Ca++ channels, induction of immediate early genes and expression of heat-shock proteins, among others, have been discussed. The contribution of the various electrophysiologic and biochemical/molecular events to the complex cascade, eventually leading to neuronal damage, is still controversial. The demonstration of viable (penumbra) tissue by positron emission tomography up to several hours after ischemic stroke renders the rationale for therapeutic interventions. A short therapeutic window of a few hours is relevant for re-establishment of perfusion; the time-dependent propagation of the ischemic penumbra suggests an extended period for effective intervention with biochemical/molecular processes.