Owing to the market competitiveness and urgent societal need, an optimum speed of drug discovery is an important criterion for successful implementation. Despite the rapid ascent of artificial intelligence and computational and bioanalytical techniques to accelerate drug discovery in big pharma, organic synthesis of privileged scaffolds predicted in silico for in vitro and in vivo studies is still considered as the rate-limiting step. C–H activation is the latest technology added into an organic chemist's toolbox for the rapid construction and late-stage modification of functional molecules to achieve the desired chemical and physical properties. Particularly, elimination of prefunctionalization steps, exceptional functional group tolerance, complexity-to-diversity oriented synthesis, and late-stage functionalization of privileged medicinal scaffolds expand the chemical space. It has immense potential for the rapid synthesis of a library of molecules, structural modification to achieve the required pharmacological properties such as absorption, distribution, metabolism, excretion, toxicology (ADMET) and attachment of chemical reporters for proteome profiling, metabolite synthesis, etc. for preclinical studies. Although heterocycle synthesis, late-stage drug modification, ¹⁸F labelling, methylation, etc. via C–H functionalization have been reviewed from the synthetic standpoint, a general overview of these protocols from medicinal and drug discovery aspects has not been reviewed. In this feature article, we will discuss the recent trends of C–H activation methodologies such as synthesis of medicinal scaffolds through C–H activation/annulation cascade; C–H arylation for sp²–sp² and sp²–sp³ cross-coupling; C–H borylation/silylation to introduce a functional linchpin for further manipulation; C–H amination for N-heterocycles and hydrogen bond acceptors; C–H fluorination/fluoroalkylation to tune polarity and lipophilicity; C–H methylation: methyl magic in drug discovery; peptide modification and macrocyclization for therapeutics and biologics; fluorescent labelling and radiolabelling for bioimaging; bioconjugation for chemical biology studies; drug-metabolite synthesis for biodistribution and excretion studies; late-stage diversification of drug-molecules to increase efficacy and safety; cutting-edge DNA encoded library synthesis and improved synthesis of drug molecules via C–H activation in medicinal chemistry and drug discovery.