The term “exosome” was coined in 1981 (Trams et al, Biochim Biophys Acta, 1981, 645:63) when the presence of “exfoliated membrane vesicles with 5-nucleotidase activity” was first reported. Since then, in the biomedical literature the term exosome has evolved to designate both the above mentioned small vesicles of endocytic origin and the 3- > 5 exonuclease complex involved in RNA processing and degradation. In the present review we will focus on the original definition of exosomes and particularly on their emerging role as intercellular signaling devices. Exosomes are secreted by a variety of cells, particularly antigen-presenting cells such as DCs, B cells and macrophages. Enriched in MHC class I and II antigens and costimulatory molecules, they are considered to be an alternative pathway of antigen delivery and presentation. The use of exosomes engineered to prime the immune system against tumor antigens is a promising new arm of cancer immunotherapy. On the other hand, exosomes released by the tumor itself may provoke a tolerogenic response. Participation of exosomes in other immune mechanisms, such as platelet activation, mast cell degranulation, germinal center reaction and engulfment of apoptotic cells has also been postulated. An evolutionary link between retroviruses and exosomes has recently been proposed. In general, viruses can use the hosts intracellular machinery for their budding, and exosomes may constitute a vehicle for transmission of pathogens and interaction with the immune system. A deeper knowledge of the cells targeted by exosomes and the mechanisms governing these interactions will give a clear picture of the role of exosomes as intercellular messengers.