Complex III deficiencies are among the least common respiratory-chain abnormalities identified to date in humans. Nevertheless, their unexplained tissue specificity and broad clinical spectrum make them a valuable model for investigating respiratory-chain diseases. In this review, we briefly discuss the properties of complex III and the assay conditions relevant to the screening of high-risk patients. We then review the most recent advances in the field, which include the characterization of several disease genes and of the corresponding clinical presentations. Finally, we discuss genetic and biochemical aspects that may help to understand complex III-associated diseases.