The capacity to injure infected cells is a widespread property of viruses. Usually, this cytopathic effect (CPE) is ascribed to viral hijacking of cellular resources to fulfill viral needs. However, evidence is accumulating that CPE is not necessarily directly coupled to viral reproduction but may largely be due to host defensive and viral antidefensive activities. A major part in this virus–cell interaction appears to be played by a putative host-encoded program with multiple competing branches, leading to necrotic, apoptotic, and, possibly, other types of cell suicide. Manifestations of this program are controlled and modulated by host, viral, and environmental factors.