The tumor microenvironment is replete with factors secreted and internalized by surrounding cells. Exosomes are nano-sized, protein-embedded, membrane-bound vesicles that are released in greater quantities from cancer than normal cells and taken up by a variety of cell types. These vesicles contain proteins and genetic material from the cell of origin and in the case of tumor-derived exosomes, oncoproteins and oncogenes. With increasing understanding of the role exosomes play in basic biology, a more clear view of the potential exosomes are seen to have in cancer therapeutics emerges. However, certain essential aspects of exosome function, such as the uptake mechanisms, are still unknown. Various methods of cell–exosome interaction have been proposed, but this review focuses on the protein–protein interactions that facilitate receptor-mediated endocytosis, a broadly used mechanism by a variety of cells.