The tumor microenvironment (TME) has recently gained significant attention as crucial to cancer treatment development, specifically cancer immunotherapy, which has also gained prominence in the last decade. TME components include both cellular (stromal cells) and noncellular components (extracellular matrix) at varying degrees, contributing to increasing tumor heterogeneity. Key among the cellular components are T lymphocytes and macrophages. Advances in tumor immunotherapies, which target immune responses generated in the TME, have shown significant improvement in the treatment of cancer alone or in combination with other immunotherapeutic agents or with alternative treatment modalities. Over the last 10 years, these advances have led to the development of the class of immunotherapies known as checkpoint inhibitors, which are emerging as the mainstay. The cytotoxic T-lymphocyte-associated protein (CTLA-4) and programmed cell death protein 1 (PD-1) are two checkpoint pathways that have been targeted. The overall function of these drugs is to generate T cell responses, which are effective against immunogenic antigens typically present on cancer cells, or to improve targeting of the cancer cells through mobilization of macrophage and myeloid-derived components to the TME to destroy the cancer. In this chapter, we discuss the TME, highlighting aspects of its architecture and focusing on how the presence or absence of tumor infiltrating lymphocytes (TILs) and programmed death-ligand 1 (PD-L1) have been used in its classification and harnessed for tumor immunotherapy. Cognizance of the fact that TILs and PD-L1 levels in the TME are just one of the possible classifications, other immunotherapeutic approaches are briefly considered.