Ceramide, a long chain sphingolipid that is generated intracellularly upon hydrolysis of membrane-associated sphingomyelin, has recently been implicated as a second messenger-like molecule that is produced distal to ligation of the tumour necrosis factor receptor type 1 (TNFR1), as well as the related Fas (CD95/Apo-1) molecule. It is well established that ligation of TNFR1 or Fas leads to apoptosis in most cases. Furthermore, it has also recently been demonstrated that exposure to cell-permeable synthetic ceramides can result in apoptosis in many cases. These and other observations have led to the hypothesis that accumulation of intracellular ceramide may be a common element of several pathways that result in apoptosis. Here we show that exposure to synthetic ceramides triggers apoptosis in the human T lymphoblastoid cell lines, CEM and Jurkat, and that overexpression of the apoptosis-repressor protein, Bcl-2, renders these cells resistant to the apoptosis-inducing effects of ceramide, as well as to several other stimuli. Since exposure to ceramides can result in either cell proliferation, differentiation, cycle arrest, or death, the level of Bcl-2 expression in a cell may be an important factor in determining the outcome of signals that result in intracellular generation of this sphingolipid.