Chromenes (benzopyrans) are privileged scaffolds that are widely distributed in a plethora of biologically active natural products, drugs and therapeutic leads. 2H-Chromenes and their benzofused derivatives are extensively distributed in nature and are considered essential for the development of new therapeutic agents for a variety of diseases. The chromene nucleus is a vital constituent of various naturally occurring and synthetic molecules with a broad range of bioactivities, such as anti-vascular, anti-microbial, antioxidant, anti-tumour, antifungal, antiviral, anti-cancer, anti-HIV, anti-tubercular, anti-coagulant, anti-inflammatory, oestrogenic, analgesic, anti-helminthic, herbicidal, anti-convulsant and anti-spasmolytic activity. Chromene constitutes the fundamental skeleton of different types of natural alkaloids, coumarins, flavonoids, polyphenols, anthocyanins and tocopherols. Recently, naturally occurring chromenes, such as wittifurans A, D, E and F, gramniphenol C, F and G, (+)-psiguadial B, parvinaphthol C, busseihydroquinone E, anthopogochromane A–C, tuberatolide B, (R)-sargachromenol, (S)-sargachromenol, obovatin, chalcones, flemingins A–C, G and H, soulamarin, lindbergin E–F and flemiphilippinones C have been isolated from various plants. This chapter not only critically reviews the recent literature reports on chromene as a privileged scaffold in medicinal chemistry, particularly, 2,2-dimethyl-2H-chromenes, natural benzochromenes and fused chromenes, but also highlights the need for further research on reported and new chromene-based phytomolecules to evaluate their possible therapeutic applications, and toxicological and particular genotoxic profiles against a wide range of diseases, especially cancer, drug-resistant microbial infections and lethal viral diseases.