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Targeting cell surface molecules is paying off. Moving beyond immune checkpoint inhibitors (ICI), targeting DLL3 with tarlatamab in previously treated ES-SCLC generated an unprecedented response. Use of a combination of vascular endothelial growth factor (VEGF)\/PD-1\/PD-L1 antibody and chemotherapy seemed more effective than ICI plus chemotherapy. Bispecific antibodies targeting PD-1\/PD-L1\/VEGF in combination with chemotherapy are being tested in the first-line setting. B7H3 and SEZ6 antibody-drug conjugates yielded encouraging results in the early phase. Modulation of epigenetic processes is being pursued for its potential to reprogram cancer cells to a disadvantage for growth and immune evasion. Due to tumor heterogeneity and plasticity, rational combinations pursuing broader cancer cell vulnerabilities are likely necessary in the future to prevent relapse. 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