This speech explores the role of Pemetrexed in treating non-squamous non-small cell lung cancer (NSCLC) with identifiable targetable mutations. It highlights the potential efficacy of Pemetrexed in both first and second-line settings after tyrosine kinase inhibitor (TKI) failure. By examining various studies on long-term response rates in NSCLC with driver oncogenes, Pemetrexed emerges as a viable therapeutic option. The speech suggests that patients with molecularly characterized NSCLC should be considered for a Pemetrexed-based treatment regimen, including its use in maintenance therapy. These findings advocate for integrating Pemetrexed-based regimens as a significant component of treatment strategies in the current landscape of targeted cancer therapy, emphasizing its value beyond conventional treatment approaches.