Our goal is to understand how the immune system is activated to effectively eliminate infected or cancer cells. We focus on dendritic cells, which have a unique ability to initiate immune responses and mobilize cytotoxic killer cells. Indeed, patients (or animals) lacking dendritic cells fail to control infections, malignancies, and auto-immune diseases. Dendritic reside in all tissues and survey the environment for signals associated with infection or cancer. In response to such signals, they sample surrounding cells and migrate to the nearby lymph nodes. In the lymph nodes, they present fragments of pathogen- or cancer-derived proteins on the cell surface in order to specifically activate only the relevant T cells. Activated T cells migrate to the inflamed tissues and rapidly kill the target cells. The molecular mechanisms involved in tissue sampling and processing of proteins for presentation to T cells remain elusive. We also have very limited understanding of how cancer-derived signals enhance or inhibit dendritic cell functions. Here, we approach these two questions using genetics, proteomics, and transcriptomics-based techniques. Better understanding of the molecular mechanisms involved in initiation of immune responses by dendritic cells is a stepping stone for rational design of more effective vaccines and anticancer therapies.