MuRF1 (TRIM63) has been long known as a critical regulator in skeletal muscle atrophy. Over two decades of research has made evident that MuRF1’s expression is critical to the development of muscle atrophy. However, the development of atrophy inhibiting pharmaceuticals targeting MuRF1 has been hindered as MuRF1’s ubiquitin E3 ligase activity remains uncharacterised. The mechanism regulating MuRF1 activity, substrate recognition, and downstream effectors are unclear. This review aims to highlight the current research of molecular mechanisms by providing insights regarding MuRF1’s cooperating UBE2s, the topology of MuRF1 ubiquitylation, and the fates of MuRF1 substrates.