Normal, bi-directional interactions between CD 40 and its natural ligand CD 154 (CD 40 ligand) are central to the generation of both T cell-dependent, humoral immune responses and cytotoxic T-cell responses. CD 40 is expressed on a broad range of hematological and epithelial malignancies. The development of monoclonal antibodies directed against CD 40 allows effective targeting of malignant cells through multiple mechanisms that include the recruitment of immune effector mechanisms such as complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, direct anti-proliferative effects on neoplastic cells and, importantly, by the activation of tumor-targeted cellular cytotoxicity. This review provides the background to the early clinical trial data that are now beginning to emerge for this potentially exciting new treatment approach.