The S6K proteins are mTOR pathway effectors and accumulative evidence suggest that mTOR/S6K signaling contributes to several pathological conditions, such as diabetes, cancer and obesity. The activation of the mTOR/S6K axis stimulates protein synthesis and cell growth. S6K1 has two well-known isoforms, p70-S6K1 and p85-S6K1, generated by alternative translation initiation sites. A third isoform, named p31-S6K1, has been characterized as a truncated type of the protein due to alternative splicing, and reports have shown its important role in cancer. Studies involving S6K2 are scarce. This article aims to review what is new in the literature about these kinases and establish differences regarding their interacting proteins, activation and function, connecting their roles in the homeostasis of the cell and in pathological conditions.