Skeletal muscle atrophy stemming from cachexia is a serious co-morbidity seen in a variety of diseases, including Cancer, Congestive Heart Failure, COPD and AIDS. Even during simple muscle inactivity, such as when a cast is put on a limb, the affected muscle can decrease by as much as 50% in mass, with a coincident decrease in functional capacity. Two E3 ubiquitin ligases – MuRF1 (Muscle RING Finger 1) and MAFbx (Muscle Atrophy Fbox protein), are transcriptionally upregulated in all physiological settings of muscle atrophy that have been analyzed. The pathways which regulate these ligases and substrates of MuRF1 – which comprise part of the skeletal muscle contractile apparatus – will be discussed; settings where MuRF1 is differentially active on its substrates suggests the possibility of an ordered breakdown pathway by MuRF1 at the contractile apparatus. The E3 ligases are regulated by the IGF1/Akt pathway, via the transcription factor Foxo. Recently, we’ve characterized additional muscle regulators which signal into this system; special focus will be given to myostatin, a TGFbeta family member which inhibits muscle differentiation, and how it itneratcts with the IGF1/Akt/TORC1 pathway.