The article discusses the development of biomarkers to guide the use of immune checkpoint inhibitors (ICIs) in cancer therapy, focusing on anti-PD1 and anti-CTLA4 therapies. It highlights the importance of understanding the mechanisms of action (MOAs) of these checkpoints and the unique biology of each. For anti-PD1 therapy, the article explores immunological, genetic, and virological criteria for biomarker development, emphasizing the role of intratumoral lymphoid infiltrates, PDL1 expression, and mutational load. For anti-CTLA4 therapy, the focus is on peripheral blood lymphocyte profiles and the diversity of immune cells. The article also discusses the challenges in developing robust biomarkers and the potential pitfalls of using PDL1 immunohistochemistry (IHC) as a biomarker. Additionally, it reviews the role of oncogenic mutations and DNA mismatch repair (MMR) deficiency in predicting response to ICIs, particularly in virus-associated cancers. Finally, the article touches on the potential of combination therapies involving ICIs and other treatments.The article discusses the development of biomarkers to guide the use of immune checkpoint inhibitors (ICIs) in cancer therapy, focusing on anti-PD1 and anti-CTLA4 therapies. It highlights the importance of understanding the mechanisms of action (MOAs) of these checkpoints and the unique biology of each. For anti-PD1 therapy, the article explores immunological, genetic, and virological criteria for biomarker development, emphasizing the role of intratumoral lymphoid infiltrates, PDL1 expression, and mutational load. For anti-CTLA4 therapy, the focus is on peripheral blood lymphocyte profiles and the diversity of immune cells. The article also discusses the challenges in developing robust biomarkers and the potential pitfalls of using PDL1 immunohistochemistry (IHC) as a biomarker. Additionally, it reviews the role of oncogenic mutations and DNA mismatch repair (MMR) deficiency in predicting response to ICIs, particularly in virus-associated cancers. Finally, the article touches on the potential of combination therapies involving ICIs and other treatments.