The CD95 system plays a crucial role in the regulation of apoptosis in particular in lymphohematopoetic cells. CD95 is expressed on many cell types including activated T and B cells. Following multimerization of CD95 by its natural ligand or agonistic antibodies, a death inducing signalling complex is formed that contains the death domains of the receptor, FADD and the recently cloned FLICE or MACH molecules. The latter initiate proteolytic cleavage of ICE/Ced-3 proteases, crucial for transmission of the apoptotic signal. The CD95 ligand is produced by activated T cells and constitutively expressed in a variety of tissues. In activated T cells, T cell receptor mediated apoptosis involves an autocrine suicide via CD95 receptor/ligand interaction. Disturbances of the CD95 system are involved in a variety of pathological conditions and human diseases. Thus, mutations of the receptor have been detected in patients with a syndrome of lymphoproliferation and autoimmunity. CD95 is constitutively expressed on the majority of acute leukemias of the T cell phenotype. A large proportion of these leukemias are also sensitive for CD95 mediated apoptosis. However, in some cases resistance to CD95 mediated cell death is found. This resistance appears not to be due to mutations of the receptor but rather be determined by an intrinsic anti-apoptotic program. Generally, members of the Bcl-2 family have been shown to block apoptosis under a variety of conditions. However, Bcl-2 expression is not correlated with resistance to CD95 mediated apoptosis in T-ALL cells. Recently we discovered that cytotoxic drugs previously thought to inhibit cellular proliferation mainly by metabolic function or DNA damage, uniformly activate the CD95 system in T cell leukemias and other tumors. Upon incubation with cytotoxic drugs such as doxorubicin, the CD95 ligand is produced and initiates the death cascade previously described as autocrine suicide or paracrine death for activated T cells. Inhibition of CD95 induced apoptosis in T cell leukemia cells leads to drug resistance. Conversely, drug resistant cells are resistant to CD95 induced apoptosis. Inhibition of ICE/Ced-3 proteases involved in the CD95 pathway also confer drug resistance to tumor cells. The discovery of cross resistance between CD95 induced apoptosis and cytotoxicity of anticancer drugs opens new perspectives for diagnosis and treatment in leukemia.