Exquisite in vitro biochemical examinations of protein ubiquitylation and degradation have historically been the dominant methods for unraveling the mechanisms of protein destruction. The study of protein abundance alterations and protein modifications, a cornerstone of protein degradation pathways, naturally lends itself to global and systematic proteomic methods to decipher the emerging complexity of protein degradation pathways. Advances in proteomic technologies have fueled an explosion of systematic and quantitative studies aimed at understanding how the proteome is shaped and regulated by ubiquitin-dependent processes. These types of studies, as well as targeted analyses of cellular pathways, have revealed that alterations in protein degradation function can have a severe impact on human health and disease. The fusion of these two themes was the focus of the January 2012 conference on proteomics of protein degradation and ubiquitin pathways (PPDUP) held in San Diego. To gain insights into both the current state-of-the-art proteomic methods to investigate protein turnover, and how protein degradation function is altered within a range of human disorders a variety of speakers revealed the many connections between altered protein degradation function and human disease. Many of the sessions were framed by a consistent focus aimed at the discovery and development of novel therapeutics targeting protein degradation pathway components to treat various human maladies ranging from cancer to heart disease.