This article discusses forms of cell cooperation involving CD4 T cells and their impact on adaptive immunity. In particular, evidence will be presented in favor of cooperation among CD4 T cells of different specificity, its molecular basis and functional significance. Th-Th cooperation, or help for helpers, will be discussed in relation to the induction of anti-tumor responses and, in converse, the generation of autoimmunity. A model is proposed where Th-Th cooperation may represent the structure/function substrate for the control of self/non-self discrimination and peripheral tolerance in vivo.