During the past decade the diagnostic use of blood volume determinations has declined as a result of the generation of largely inaccurate results and inappropriate normalization and interpretation. After historical development of more than 50 years, current methodology employs 125I-labeled human serum albumin and 51Cr-labeled red blood cells to determine plasma volume and red cell volume, respectively. Accurate blood volume determinations require (1) abandoning the use of the mean body hematocrit:venous hematocrit ratio and using simultaneous independent measurements of both volumes; (2) delaying multiple postinjection patient samples until complete mixing and equilibration are complete; (3) backextrapolation of plasma concentrations of 125I to account for albumin loss from the plasma, and, rarely, back-extrapolation of red cell concentrations to account for dilution by red cells transfused during the procedure; (4) normalization of volumes by adjusting patient weight to normal correspondence with lean tissue mass, whenever necessary. A rapid, routine method that fulfills these four requirements is presented. A number of surgical and medical conditions in which blood volume determinations are very useful in diagnosis and therapy are discussed. Recently developed techniques for blood volume measurements include neutron acativation analysis and fluorescent excitation analysis. Correct normalization of accurate blood volume measurements will provide a valuable service to the entire medical community.