Immuno-oncology has revolutionized the treatment of metastatic non-small cell lung cancer (mNSCLC) since the approval of immunotherapy by the U.S. FDA in 2015. Despite the advancements, outcomes for patients have room for further improvement. Combination therapies have shown promise in overcoming resistance and improving outcomes. This review focuses on current immunotherapy-based combination approaches, reported and ongoing trials, as well as novel combination strategies, challenges, and future directions for mNSCLC treatment. We summarize approaches in combination with chemotherapy, novel immune checkpoints, tyrosine kinase inhibitors and other strategies including vaccines, and radiation therapy. The promise of biomarker-driven studies to understand resistance and design multi-arm platform trials that evaluate novel therapies is becoming of increasing relevance with the ultimate goal of administering precision immunotherapy by identifying the right dose of the right combination for the right patient at the right time.