A significant portion of bioactive secondary metabolites, be it sesquiterpenes, polyketides or alkaloids are endowed with reactive functionalities that can engage in covalent interactions with the targeted protein.Despite the clinical successes of covalent inhibitors, drug development efforts have generally shied away for this mode of inhibition.Our efforts towards the synthesis of natural product-inspired covalent inhibitors and the discovery of new ones by rational design of nucleic acid encoded chemistry will be discussed.