The nucleotide binding sites of kinases are compact and highly druggable, and therefore differ from the kinds of targets that are typically thought of as requiring a beyond Rule-of-Five inhibitor chemotype such as high molecular weight macrocycles. Nonetheless, there are now multiple examples of marketed Type I kinase inhibitor drugs that are macrocycles. As shown in Figure , these compounds occupy a region in macrocycle structure-property space that is distinct from the regions occupied by macrocyclic drugs that bind to other target classes. In particular, these approved kinase inhibitor drugs that are macrocycles tend to have smaller rings and lower molecular weight compared to other macrocyclic drugs, and unlike these other drugs are generally Rule-of-Five compliant Multiple examples show that acyclic inhibitors that bind the kinase with a U-shaped geometry can often be cyclized to give macrocyclic inhibitors. Converting a suitable acyclic inhibitor to a macrocycle can be guided by an X-ray crystal structure of the bound ligand, or even by a modeled structure. The examples described above show that the resulting macrocycle will often have distinct properties, compared to the acyclic precursor, which can include a higher affinity, a distinct selectivity profile, and improved ADME properties. A macrocycle thus places the medicinal chemist in different property space, as well as a different IP space, compared to acyclic chemotypes, potentially enabling the discovery of compounds with uniquely favorable properties.