The acyl Sonogashira reaction represents an extension of Sonogashira cross-coupling to acid chlorides which replace aryl or vinyl halides, while terminal acetylenes are used as coupling partners in both reactions. The introduction of a carbonyl functional group on the alkyne backbone determines a radical change in the reactivity of the products. Indeed, α,β-alkynyl ketones can be easily converted into different heterocyclic compounds depending on the experimental conditions employed. Due to its potential, the acyl Sonogashira reaction has been deeply studied with particular attention to the nature of the catalysts and to the structures of both coupling compounds. Considering these two aspects, in this review, a detailed analysis of the literature data regarding the acyl Sonogashira reaction and its role in the synthesis of several heterocyclic derivatives is reported.