Dendritic cells (DCs) play a critical role in immune responses by efficiently capturing and presenting antigens to T cells. Our goal is to decipher the molecular details involved in presentation of exogenous antigens on MHC class I (cross-presentation) and in generation of co-stimulatory signals that determine T cell fate (cross-priming or cross-tolerance). We employ novel assays in genetic screens to identify the molecular machinery involved and use in vivo models of disease to demonstrate the relevance of the pathways during initiation of immune responses. In this talk, I will discuss our work on the role of perforin-2 in endosomal escape and delivery of antigens for cross-presentation as well as our work to identify cancer-derived danger signals that facilitate cross-priming.