The complexity of T cell activation to maintain homeostasis and provide host defense is highlighted by the intricate step-wise process which is coordinated by multiple cell types. Crucial to T cell activation is the requirement of antigen-presenting cells (APCs) such as macrophages at each step of the activation and effector stages. Macrophages are central regulators in T cell activation and are involved in each step including initiating the series of events leading to T cell activation. Macrophages identify and present foreign antigens in classes I and II major histocompatibility complexes (MHC) to T cells, which recognize the MHC-antigen complex through their T cell receptor. This initial step is all in vain if additional costimulatory and cytokine signaling does not occur concurrently. Macrophages can mediate and provide the required costimulatory signaling and cytokine secretion required for effective T cell activation. While other cell types, especially other APCs, may be capable of playing a role during different stages of T cell activation, this review will focus on how macrophages can modulate T cell activation and effector function. This is in no way an attempt to minimize the role of other APCs but instead to bring to light to the role macrophages can play during this process. Here, the role macrophages play in cancer to either activate or inhibit T cells based on macrophage phenotype, costimulatory molecules, and cytokine secretion is highlighted as an example of how macrophages can significantly alter T cell activation and effector function in human disease.