Apoptosis, or programmed cell death, is a complex, genetically-determined process involved in the development and maintenance of homeostasis in multicellular organisms. Dysregulation of apoptosis has been implicated in a number of diseases, including cancer and autoimmune disease. Thus, the investigation of apoptotic regulation has evoked considerable interest. Many apoptotic proteins have been shown to be post-translationally modulated, such as by protein cleavage, translocation, protein-protein interaction, and various post-translational modifications, which fall precisely within the range of proteomic analysis. Recently, contemporary proteomic technologies have achieved significant advances and have accelerated research in functional and chemical proteomics, which have been applied to the field of apoptosis research and have the potential to be a driving force for the field. This review highlights some of the major achievements in the application of proteomics in apoptosis research and discusses new directions and challenges for the near future.