T-lymphocytes play a critical role in cancer immunity as evidenced by their presence in resected tumor samples derived from long-surviving patients, and impressive clinical responses to various immunotherapies that reinvigorate them. Indeed, tumors can upregulate a wide array of defense mechanisms, both direct and indirect, to suppress the ability of Tcells to reach the tumor bed and mount curative responses upon infiltration. In addition, patient and tumor genetics, previous antigenic experience, and the microbiome, are all important factors in shaping the T-cell repertoire and sensitivity to immunotherapy. Here, we review the mechanisms that regulate T-cell homing, infiltration, and activity within the solid tumor bed. Finally, we summarize different immunotherapies and combinatorial treatment strategies that enable the immune system to overcome barriers for enhanced tumor control and improved patient outcome.