Type 5 tartrate-resistant acid phosphatase (TRACP) is a sensitive and specific cytochemical marker for hairy cell leukemia and for differentiated cells of the mononuclear phagocyte lineage. Recently serum TRACP activity has been validated as a relevant clinical biomarker of osteoclasts and bone resorption. Advances in knowledge about TRACP enzymology, structure, function and molecular regulation have been instrumental for our appreciation that TRACP isoforms 5a and 5b have different clinical significance. Osteoclastic TRACP5b has diagnostic and prognostic applications in osteoporosis, cancers with bone metastasis, chronic renal failure and perhaps other metabolic and pathologic bone diseases. Serum TRACP5a, on the other hand, is a measure of activated macrophages and chronic inflammation. This review briefly summarizes the important basic scientific developments that have led up to the refinement of serum TRACP5b immunoassay and its application as a biomarker of metabolic and pathologic bone disease.