The incidence of type 2 diabetes mellitus (T2D) is growing rapidly due to aging, urbanization, changes in lifestyle, and increasing prevalence of obesity. In T2D, chronic hyperglycemia leads to macro and micro vascular complications, which currently are serious problem for health systems worldwide. The complexity of T2D and its complications requires study skills of high performance that provide important information in the understanding of the pathophysiology of the disease and biological pathways involved in development of T2D and its complications. In this work we describe the recent contributions of proteomics in the study of T2D and discuss its importance in the identification of therapeutic targets and biomarkers that help to improve the diagnosis of T2D, monitor the disease progression, and the development of new drugs to improve treatment and reduce its complications.