The ultimate outcome of alloreactivity versus tolerance following transplantation is potently influenced by the constellation of cosignaling molecules expressed by immune cells during priming with alloantigen, and the net sum of costimulatory and coinhibitory signals transmitted via ligation of these molecules. Intense investigation over the last two decades has yielded a detailed understanding of the kinetics, cellular distribution, and intracellular signaling networks of cosignaling molecules such as the CD28, TNF, and TIM families of receptors in alloimmunity. More recent work has better defined the cellular and molecular mechanisms by which engagement of cosignaling networks serve to either dampen or augment alloimmunity. These findings will likely aid in the rational development of novel immunomodulatory strategies to prolong graft survival and improve outcomes following transplantation.