Mass balance is an important concept in pharmaceutical development, but it often proves challenging to assess accurately. This article explores the various methods by which mass balance can and should be measured, expressed, and evaluated in conjunction with degradation chemistry. Causes of mass-balance issues and potential solutions are summarized, as are the advantages and the disadvantages of various detection strategies. The importance of reactants other than the parent drug, reaction stoichiometry, response factors, and assay variability are discussed, and recommendations for obtaining reliable and informative mass-balance information are provided.