Natural killer T (NKT) lymphocytes mediate a rapid reaction to the glycolipid drug alpha-galactosylceramide (alpha GalCer), which triggers release of large amounts of cytokines into the serum within 12 h, starting with interleukin 4 (IL-4). When alpha GalCer is administered to mice on dendritic cells (DCs) instead, the response is more prolonged (>4 days) and marked by a large expansion in IFN-gamma-producing NKT cells as well as greater resistance to metastases of the B16 melanoma. Nevertheless, DCs from mice given free alpha GalCer are able to induce strong IFN-gamma-producing NKT responses when transferred to naïve mice, but not when transferred to alpha GalCer-treated recipients. In the latter, the NKT cells are energized and can respond to glycolipid only in the presence of supplemental IL-2. Therefore, when alpha GalCer is selectively targeted to DCs, mice develop a stronger, more prolonged and effector type of NKT response, but this response can be blocked by the induction of anergy after presentation of alpha GalCer on other cells.