MCL1 is a pro-survival BCL2-family protein that is frequently overactive in cancers and can promote resistance to treatment, making it an attractive target for cancer therapy. MCL1 turnover is often tightly controlled through proteasomal degradation, with several ubiquitin-dependent and -independent mechanisms described. One stimulus that promotes MCL1 degradation is an engagement by its BH3-only protein ligand NOXA, but how this occurs is unknown. We found that when engaged by NOXA, MCL1 was targeted to the proteasome through ubiquitination on two lysine residues. To identify genes required for NOXA-induced MCL1 degradation, we carried out a genome-wide loss-of-function CRISPR/Cas9 screen using cells co-expressing NOXA and a GFP-MCL1 reporter. We identified several genes including mitochondrial ubiquitin E3 ligase MARCH5, the ubiquitin E2 conjugating enzyme UBE2K and the mitochondrial protein MTCH2, each of which was confirmed to be critical for NOXA-mediated MCL1 degradation. MARCH5 and UBE2K are enzymes known to belong the ubiquitin proteasome pathway, but MTCH2 has not previously been implicated in controlling protein turnover. MTCH2 has a role in metabolism and promotes mitochondrial localization of certain BCL2 family proteins. Our data expand on its links to BCL2-regulated apoptosis and identify a previously unappreciated role for MTCH2 in turnover of the MCL1:NOXA complex by MARCH5. We show that this pathway is a major determinant of MCL1 levels in cells that express abundant NOXA. Taken together, our data provide new insights into how MCL1 turnover is controlled.