Poly-ubiquitin chains are post-translational modifications commonly used by the ubiquitin-proteasome system to mark proteins for degradation. The regulation of protein degradation plays an important role in regulating muscle cell size, a cellular process balanced by protein synthesis and catabolism. MafBx/Atrogin-1, a muscle-specific F-box protein, is a principle component of the SCFatrogin-1 ubiquitin ligase complex that ubiquitinates and targets calcineurin for degradation, a key regulatory protein involved in pathologic hypertrophy. We have recently described a novel role for this ubiquitin ligase as a co-activator of the FOXO transcription factors through the catalysis of non-canonical poly-ubiquitin chain formation on FOXO proteins, an event that is sufficient to block Akt-dependent pathways involved in physiologic hypertrophy. In context with other reports describing the regulation and role of FOXO transcription factors, we present a working model for the role of atrogin-1 in both physiologic and pathologic hypertrophy.