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Activating epidermal growth factor receptor gene mutations (EGFRm) are relatively common in non-small cell lung cancer (NSCLC) and are predictive of superior outcomes with EGFR tyrosine kinase inhibitors (TKIs). Eventually, acquired genetic or phenotypic resistance overcomes EGFR TKI therapy. Heterogeneity of acquired anti-EGFR resistance mechanisms is increasingly described, presenting a significant challenge in their clinical management. Here, we report a rare case of concurrent acquired EGFRT790M and small cell lung cancer transformation in a patient with EGFR exon 21-L858R mutant lung adenocarcinoma, following treatment with a second-generation EGFR TKI. The case highlights the clinical significance of serial EGFR genotyping with peripheral ctDNA alongside targeted biopsies, for the detection of genetic and phenotypic resistance mechanisms to EGFR TKIs, which can occur concurrently. This case provides further evidence in favour of upfront treatment approaches that target the heterogeneity of acquired anti-EGFR resistance mechanisms, such as experimental combinations of cytotoxic chemotherapy with a third-generation EGFR TKI.