The spread of cancer to bone is considered a terminal event. Two main types of bone metastasis can manifest, i.e. osteoblastic and osteolytic. Irrespective of metastatic type, uncoupled bone remodeling is always present and perpetuates a vicious cycle of excess bone resorption and destruction. Biochemical markers of bone metabolism are potentially useful to diagnose metastatic bone disease and to monitor treatment response in cancer patients. Tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) is a biochemical marker of osteoclast number and activity. Mounting evidence has demonstrated serum TRACP 5b as a useful marker of bone resorption and therefore bears clinical applicability in diagnosis and management of metabolic and pathologic bone diseases. Serum TRACP 5b is among one of the many bone resorption biochemical markers that have been studied to be a surrogate marker of bone metastasis in cancer patients. Its serum level may reflect the degree of lytic bone metastasis and, in turn, the tumor burden within the bone milieu. This review summarizes the development of specific immunoassays for serum TRACP 5b as well as current evidence for its exploitation as a biomarker for diagnosis, treatment response, and prognosis in various cancers with high incidence of bone metastasis including breast, prostate, lung, and multiple myeloma.