The investigations in the chemistry and biology of α-pyrone (2-pyrone) are of vital importance as they constitute an essential pharmacophore in many naturally occurring and biologically active synthetic agents. They are a promising class of biorenewable platform chemicals that provide access to an array of chemical products and intermediates. Literature survey reveals that a simple change in the substitution pattern on the 2-pyrone ring system often leads to diverse biological activities. In this review, we present a brief overview of 2-pyrone pharmacophore followed by highlighting their pharmacological properties and potential applicability till date. Particular attention is focused on the distinctive chemotherapeutic activities of 2-pyrones as anti-HIV, anti-TB and anti-cancer agents followed by their potential role against neurodegeneration, hypercholesterolemia, microbial infections, chronic obstructive lung disease, inflammation, antinociception and immunomodulation. Since 2005, when 2-pyrones came in limelight, their detailed pharmacological activities have been well documented. This review has mainly been prepared on the basis of original reports published in recent two decades with an aim to attract the attention of researchers towards this versatile scaffold for future endeavors that may lead to the development of potential drug candidates against above diseases.