Covalent conjugation of proteins with ubiquitin is one the most important 
post-translational modifications because it controls intracellular protein 
trafficking typically resulting in protein degradation. Frequently ubiquitinated 
proteins are targeted to the proteasome for degradation in the cytosol. However, 
ubiquitinated membrane bound proteins can also be targeted for endocytosis and 
degradation in the lysosome. Ubiquitin-dependent degradation pathways have clear 
cancer relevance due to their integral involvement in protein quality control, 
regulation of immune responses, signal transduction, and cell cycle regulation. 
In spite of its fundamental importance, little is known regarding how proteins 
are specifically identified for ubiquitin-dependent degradation. In this article 
we review a newly discovered family of viral and cellular ubiquitin ligases 
called MARCH proteins. Recent studies of MARCH proteins define new paradigms 
showing how ubiquitin E3 ligases determine the intracellular location and fate 
of proteins.