Approximately 10% of -activating mutations occur as in-frame insertion mutations in exon 20 of the kinase domain ( ins20). ins20 mutations have not demonstrated the same sensitivity to early generations of EGFR tyrosine kinase inhibitors (TKI) as canonical activating mutations such as del19 and L858R. Development of effective therapies for this subset of patients has been challenging, but recent years have seen more rapid progress in these efforts. In this review, we describe the molecular and clinicopathologic features of ins20 mutations and summarize recent data on emerging therapies for patients with this subtype of -mutant non-small cell lung cancer (NSCLC). SIGNIFICANCE: When activating mutations in were first discovered in lung cancer, the lack of sensitivity of tumors harboring ins20 mutations to early-generation EGFR TKIs resulted in this subset of -mutant tumors being initially classified as an untargetable or intrinsically resistant subpopulation. In addition, the diversity of mutations within exon 20 and resultant challenges identifying them on routine clinical genotyping tests led to underestimation of their frequency. However, recent scientific progress in targeting ins20 mutations as well as more effective identification of this clinical cohort has enhanced our ability to develop effective therapies for patients with this subtype of -mutant NSCLC.