Cross-priming is the process whereby professional APC, mainly dendritic cells (DC), prime T cells by presenting antigens processed from proteins of other cells such as tumor cells or virus-infected cells. It has been argued that the importance of cross-priming of CD8(+) CTL responses has been overemphasized, despite strong evidence that these mechanisms operate when infectious organisms, tumors or self antigens cannot efficiently access the biosynthetic MHC class I processing pathway of DC. Since DC are ideally equipped to capture exogenous antigen and also, particularly in the mature state, express costimulatory molecules, it is difficult to distinguish whether effects are due to cross-presentation, costimulation, or both. Whether cross-priming or cross-tolerance occurs depends on the maturation state of the DC, as well as the levels of MHC class I-bound peptides they present. Cross-presentation of tumor-derived antigens has been demonstrated but, importantly, requires adequate APC activation to prime CTL responses. Similarly, cross-presentation of antigens from infectious organisms appears to be common, and frequently leads to cross-priming. Interactions between cross-presenting DC, CD4(+) cells and CD8(+) T cells in the establishment of immunological memory are still not well defined. Experiments utilizing DC depletion are needed to further examine the role of processes such as cross-priming and costimulation in the immune response.