Complexes of two or more proteins form many, if not most, of the intracellular “machines” that execute physical and chemical work, and transmit information. Complexes can form from stochastic post‐translational interactions of fully formed proteins, but recent attention has shifted to co‐translational interactions in which the most common mechanism involves binding of a mature constituent to an incomplete polypeptide emerging from a translating ribosome. Studies in yeast have revealed co‐translational interactions during formation of multiple major complexes, and together with recent (...) mammalian cell studies, suggest widespread utilization of the mechanism. These translation‐dependent interactions can involve a single or multiple mRNA templates, can be uni‐ or bi‐directional, and can use multi‐protein sub‐complexes as a binding component. Here, we discuss benefits of co‐translational complex assembly including accuracy and efficiency, overcoming hidden interfaces, localized and hierarchical assembly, and reduction of orphan protein degradation, toxicity, and dominant‐negative pathogenesis, all serving to improve cell fitness. (shrink)