Proteomic technologies now enable the rapid quantification of thousands of proteins across a genetically diverse population. Integration of these data with genomics and phenomics using quantitative trait loci mapping and correlation network analysis is a powerful approach to identify new regulators of economically important or disease-relevant phenotypes. Here, I present an overview of the exciting field of proteome-wide systems genetics and showcase our latest analysis of >100 extensively phenotyped inbred mouse strains. These strains display extraordinary diversity in various phenotypic responses, and our analysis has pinpointed the underlying genetic variants and proteins driving these complex traits. Specifically, we focus our analysis on liver and skeletal muscle, and identify several novel regulators of complex metabolic traits including lipid metabolism and muscle contractile function, respectively.