In the relatively young but expanding field of irreversible kinase inhibitor drug discovery, two main developments are of central importance: the first wave of low molecular weight reversible protein kinase inhibitors approved by the FDA for oncology indications over the past decade, and the renewed interest in covalent binding drugs due to a better understanding of their benefits and the approval of effective and safe covalent drugs. The therapeutic applicability of irreversible binding kinase inhibitors depends on whether the covalent bond can be confined solely to the protein kinase of interest, balancing treatment and toxicity to achieve a therapeutic window. This Perspective aims to give a comprehensive account from a medicinal chemist's point of view on the progress of irreversible kinase inhibitor drug discovery, reviews the "state of the art" by means of reported irreversible kinase inhibitor profiles and their chemical structures, highlights the potential upsides and pitfalls associated with this concept, and provides a general understanding of the differences with respect to conventional drug discovery as well as the future potential of this approach.