Abstract: The biogenesis of the inner mitochondrial membrane enzyme cytochrome c oxidase (COX) is a complex process that requires the actions of ancillary proteins, collectively called assembly factors. Studies with the yeast Saccharomyces cerevisiae have provided considerable insight into the COX assembly pathway and have proven to be a fruitful model for understanding the molecular bases for inherited COX deficiencies in humans. In this review, we focus on critical steps in the COX assembly pathway. These processes are conserved from yeast to humans and are known to be involved in the etiology of human COX deficiencies. The contributions from our studies in yeast suggest that this organism remains an excellent model system for delineating the molecular mechanisms underlying COX assembly defects in humans. Current progress suggests that a complete picture of COX assembly will be achieved in the near future.