Delayed neuronal death or incomplete brain infarction was firstly described by two independent groups of researchers, which noted that in case of middle cerebral artery permanent and temporary occlusion two different types of lesions develop in the brain. Permanent occlusion results in infarction and coagulation necrosis. Significantly different brain lesion appears after short-term (< 30 min) middle cerebral artery occlusion followed by a long-term survival (up to 28 days). In these experiments the volume of incomplete infarction or the size of selective neuronal damage depends on time elapsed after the occlusion is removed. The authors suggest that the selective neuronal death in the areas of incomplete infarction is caused by apoptosis. Applying various methods of neuroimaging and ultrastructural study of tissue damage, the authors concluded that neuronal death in the ischemic penumbra occurs by two different mechanism. Necrosis develops promptly in the center, while apoptosis happens later in the margin of the penumbra. In experimental ischemic models, production of interleukin-1 beta and tumor necrosis factor-alpha activate the macrophagal NO-synthase (NOS-2), that leads to long-lasting NO generation. The latter causes necrosis or apoptosis depending on place of NO generation, on concentration, on glucose and growth factor quantities in paracrine media and at last on interaction and ratio between NO and superoxide anione (NO/O2-) ion concentration. NO mediated apoptosis comprises the upregulation of tumor suppressor protein P-53, activation of caspases, chromatin condensation, ladder-like fragmentation of DNA and alterations in the expression of apoptosis-associated proteins which belong to BCL-2 family. The activation of caspases is the critical signal for apoptosis. Experimental studies proved, that inhibition of caspases blocks neuronal death and diminishes the size of infarction in temporary and permanent focal cerebral ischemic rat models. If we combine antiexcitotoxic and antiapoptotic strategies by application of caspase we would significantly enlarge therapeutic window and such combinations has to become the central area of further investigations.