Cytotoxic T lymphocytes (CTL) were generated in vitro against syngeneic spleen cells conjugated with a number of different haptens: trinitrophenyl (TNP-self), two different isomers of fluorescein isothiocyanate and I-AEDANS (AEDANS self). Genetic control of CTL responses to these haptens was compared. H-2(k,a) and H-2(b,d) mouse strains were the respective genetic high and low responders to haptens which conjugate to -NH2 groups. The reverse genetic pattern was observed for CTL responses to hapten-self which conjugate to -SH groups. These differential response patterns raise some interesting possibilities concerning genetic control of immune responses and the self determinants recognized. The role of helper T cells in Ir gene control and hapten specificity was also studied for the above haptens. Ir gene defects were detected at the helper cell level and in CTL precursors or accessory cells. Activation of CTL helpers was found to be specific, but once activated, these helper effects were non-specific.