There is an urgent need for improved diagnostics and therapeutics for acute ischemic stroke. This is the focus of numerous research projects involving in vitro studies, animal models and clinical trials, all of which are based on current knowledge of disease mechanisms underlying acute focal cerebral ischemia. Insight in the chain of events occurring during acute ischemic injury is essential for understanding current and future diagnostic and therapeutic approaches. In this review, we summarize the actual knowledge on the pathophysiology of acute ischemic stroke. We focus on the ischemic cascade, which is a complex series of neurochemical processes that are unleashed by transient or permanent focal cerebral ischemia and involves cellular bioenergetic failure, excitotoxicity, oxidative stress, blood-brain barrier dysfunction, microvascular injury, hemostatic activation, post-ischemic inflammation and finally cell death of neurons, glial and endothelial cells.