The ribosomal protein S6 kinases (S6Ks) are downstream effectors of signaling pathways involved in the regulation of cell growth, cell cycle progression, and cell proliferation. Studies have shown that S6K1 and S6K2 are differentially regulated and S6K2 likely has distinct functions from that of S6K1. Although the kinases share 70% identity overall, the N- and C-termini between the kinases are divergent and may help to explain some of the observed differences. The regulatory mechanisms that contribute to these differences are unclear, however, and warrant further examination. This study focused on the structural differences between S6K1 and S6K2, reasoning that structure dissimilarity correlates with differences in function and/or regulation. To this end, chimeras of S6K1 and S6K2 were generated by swapping different regions between the kinases to elucidate how each region contributes to kinase behavior and characteristics. The results suggest that, for both S6K1 and S6K2, it is the termini, rather than the catalytic domain, that are the major contributors to the behavior and characteristics typically observed by each of these kinases.