Glucosylceramide synthase (GCS) is an enzyme inherent to ceramide metabolism. The enzyme catalyzes the transfer of glucose to ceramide, the first committed step in glycolipid biosynthesis. Known for many years as a branch point enzyme directing synthesis of cerebrosides and gangliosides, GCS has recently been implicated in the cytotoxic response of cancer cells to chemotherapy. With ceramide now occupying a central role in the signaling mechanisms of apoptosis, the position of GCS as sentry is perhaps not unexpected. In particular, it has been recognized that the toxic response of cells to chemotherapy is impaired when GCS activity is elevated and heightened when GCS activity is blocked. Herein we review the control points of ceramide metabolism with special regard to GCS and the cytotoxic response.