Recent clinical success of immunotherapies targeting solid malignancies depend on the activity of T cells that express a tumor-reactive T cell receptor (TCR). The infusion of T cells that express tumor-reactive TCRs as well as immune checkpoint blockade approaches that unleash endogenous tumor-reactive T cells have shown therapeutic efficacy against several solid tumor indications. However, these striking clinical outcomes can drive both tumor cell autonomous and non-autonomous escape from T cell surveillance. Primary mechanisms include the selection of tumor cells with defective antigen processing/presentation and the induction of a hyporesponsive T cell state called T cell exhaustion. Strategies that are designed to overcome tumor escape must be tested and tailored to cell therapeutic platforms as the hierarchy of obstacles in the suppressive tumor microenvironment may be distinct from endogenous T cells. Durable cell-based therapies must be designed to anticipate and overcome escape and may necessitate combinations that support altering the suppressive tumor microenvironment.