The CD95 (Apo-1/Fas) receptor-ligand system is one of the key regulators of apoptosis and is particularly important for the maintenance of lymphocyte homeostasis. There is now broad evidence that susceptibility of tumor cells towards CD95-mediated apoptosis is largely reduced. In the human, germline and somatic mutations of the CD95 gene are associated with a high risk of both lymphoid and solid tumors. Based on these observations a new concept defining CD95 as a tumor suppressor gene is discussed. In addition to CD95, its natural ligand (CD95L) is also implicated in malignant progression. Compared to their nonmalignant counterparts, malignant cells frequently exhibit aberrant de novo expression of CD95L and are able to induce CD95L-mediated apoptosis in bystander cells. The role for neoplastic CD95L expression in local tissue destruction, invasion, and metastatic spread has been established for many tumor types. CD95L expression by malignant cells may counteract the host's antitumor immunity and favors immune escape of the tumor. On this basis, the significance of loss of CD95 and gain of CD95L expression for tumor progression is discussed.