Our experiments reveal that application of several minor H antigen—disparate skin grafts to adultXenopusover an 18-month period can lead to in vitro generation of CML reactivity toward these minor antigens. Furthermore, we demonstrate that, following MHC-disparate skin graft rejection, adult effectors can efficiently kill both adult and larval donor-strain targets; this killing is MHC-specific and requires MLC restimulation with cells syngeneic to the skin graft donor. The ability to kill larval lymphoblasts, which have been shown elsewhere to be MHC class I-negative but class II-positive, suggests the probable importance of class II—restricted killing in this species.