The ability of sophisticated proteomic approaches to scrutinize the dynamic nature of protein expression, cellular and subcellular protein distribution, post-translational modifications, and protein–protein interactions has culminated in the identification of many potential new therapeutic targets and an abundance of cancer-related biomarkers. From a proteomics perspective, amongst the most under-studied diseases are bone cancers, such as myeloma, osteosarcoma and breast and prostate cancer bony metastases. This review focuses on the recent advances in proteomic technology that have thrust the skeletal cancer field into this exciting age of proteomics, and highlights the future work that is required to adapt this technology to specifically interrogate the skeletal consequences of malignancy.