Measurement of cobalt (Co) concentrations in periprosthetic tissues and body fluids of failed cobalt-chromium alloy implants can be helpful in assessing whether or not metal-induced cytotoxicity played a role in prosthetic revision decisions. Samples should be frozen soon after collection at explant surgery for later analysis by inductively coupled plasma-mass spectrometry (ICP-MS) with interference reduction technology. Metal ions of Co are rapidly bound to proteins and other organic molecules in periprosthetic fluids, which can limit tissue uptake and toxicity in most circumstances. New methods combining size exclusion chromatography and ICP-MS can now separately quantify various protein-bound fractions and free ions and can assess the Co binding capacity of periprosthetic fluids and blood potentially to identify individuals more susceptible to cytotoxic responses. In periprosthetic tissues, split sample analyses for histopathology and total Co following acid digestion can also provide insights on degree of tissue penetration and metal-associated cytotoxicity. Standardization of ICP-MS analytical procedures for measuring relatively low tissue or fluid concentrations of total Co (e.g., less than 5 ppb) is needed because methodology and equipment differences among clinical laboratories are associated with inconsistent accuracy. This concern is underscored by suggestions that clinical decisions about excessive wear or risk of revision decisions (or both) should be based on blood total Co levels at or below 5 ppb. Literature references to Co “metal ion concentrations” are technically misleading because the toxicologically relevant free ions are not actually quantified, and both synovial fluids and blood may have a renewable, high capacity for rapid protein binding that limits the potential for clinically important cytotoxicity to periprosthetic tissues and distant organs in most cases. More detailed research to discern molecular forms of Co is needed to elucidate factors and circumstances that substantially reduce protein binding and demonstrate correlations between free Co concentrations and clinically important cytotoxicity.