Proteomics has emerged as an invaluable tool in the quest to unravel the biochemical changes that give rise to the hallmarks of cancer. In this review, we present the advances and challenges facing proteomics technology as applied to cancer research, and address how the information gathered so far has helped to enhance understanding of the mechanisms underlying the disease and contributed to the discovery of biomarkers and new drug targets. We conclude by presenting a perspective on how proteomics could be applied in the future to determine prognostic biomarkers and direct strategies for effective cancer treatment.