Although it was first described in 1989, our understanding of coenzyme Q₁₀ (CoQ₁₀) deficiency is only now coming of age with the recent first description of the underlying molecular defects. The diverse clinical presentations, classifiable into four major syndromes, raise the question as to whether the deficiencies are primary or secondary. Recent studies, including the one by Mollet, Rötig, and colleagues reported in this issue of the JCI, document molecular defects in three of the nine genes required for CoQ₁₀ biosynthesis, all of which are associated with early and severe clinical presentations (see the related article beginning on page 765). It is anticipated that defects in the other six genes will cause similar early-onset encephalomyopathies. Awareness of CoQ₁₀ deficiency is important because individuals with primary or secondary variants may benefit from oral CoQ₁₀ supplementation.