The CD40 cell surface receptor is required for normal function of the immune system and is a positive regulator of cell survival for normal B-lymphocytes. However, there is evidence to support both pro- and anti-apoptotic functions for CD40 in malignant B-cells and epithelial cancers. There is increasing interest in the potential of CD40 activating agents as novel therapies for cancer and it is essential to understand the differential response of malignant cells, to inform the design of trials. Here we review the current understanding of differential responses to CD40 activation and apoptosis controlling proteins regulated by CD40 that might account for these effects.