Transforming growth factor-beta (TGF-beta) superfamily signaling pathway and its ligands are essential regulators of cellular processes such as proliferation, differentiation, migration, and survival. Alteration of this pathway results in uncontrolled proliferation and cancer progression. This review focuses on a specific member of the TGF-beta superfamily: activin-betaC. After its initial discovery, activin-betaC has been considered non-biologically relevant. Therefore, for years several experimental designs have ignored the potential contribution of this molecule to the final biological outcome. Here we focus on recent advances in the activin field, with a particular emphasis on activin-betaC, its antagonistic mechanism, and the physiological relevance of activin-betaC actions in reproductive and cancer biology. Covering a novel and previously unexplored function of activin-betaC on cancer associated weight loss and muscle metabolism, this review suggests an imminent need to re-evaluate the function of activin-betaC in biological systems and advances the understanding of how activin-betaC antagonizes the activin signaling pathway. Thus, challenging activin biologists to consider the impact of activin-betaC when interpreting their work.