The lymphocyte's decision between tolerance and immunity/autoimmunity is regulated at many levels. Two important parameters in this decision are the maturation state of the antigen presenting cells (APCs) and the amount of self antigen that is detected by the immune system. Maturation of APCs occurs as a consequence of signals received by the innate immune system and may lead to the breakdown of tolerance. Particularly relevant to this process are the Toll-like receptors and mechanisms of cross presentation of self antigens. In addition, genetic alterations in a variety of cell surface receptors, signalling components and regulators of apoptosis/survival can break tolerance and lead to autoimmunity in vivo.