Improved understanding of the factors influencing reactivity and emergence of new types of warheads in the form of targeted covalent inhibitors (TCIs), represent a promising avenue within drug discovery, particularly in targeting proteins previously deemed 'undruggable'. Over 40 covalent drugs are currently under clinical development and many previously so called "undruggable" targets and mechanisms of resistance have now been effectively tackled by covalent compounds. Recently developed and FDA approved TCIs, AMG-510 (sotorasib) and MRTX-849 (adagrasib), effectively engage Cys12 of KRas G12C , a famously difficult target implicated in 40% of lung cancers. Additionally, ibrutinib, a first-in-class inhibitor known to successfully bind to Cyst of Bruton's tyrosine kinase (BTK), which is linked to overexpression of B cells in B cell cancers, has FDA approval for lymphoma. Other FDA approved drugs such as Aspirin, Penicillin G, and Fosfomycin are all reported to engaged targets via covalent interaction .