There are different concepts that relate to T-cell hyporesponsivity, such as ignorance, tolerance, anergy, aging, and exhaustion. Among these, T-cell exhaustion is a rather complicated phenomenon that denotes the stepwise deterioration of T-cell functioning, which may or may not result in physical deletion of the T-cells. It has been first described in a model of persistent infection by lymphocytic choriomeningitis virus (LCMV). However, it was later redefined in the context of cancers. While there is a partial overlap between these two scenarios of exhaustion, exhaustion processes are formed differently in the tumor microenvironment (TME). The significance of exhaustion mechanisms has been demonstrated in both solid and nonsolid cancers. There are different exhaustion biomarkers, such as PD-1, Tim-3, CD39, TIGIT, Lag-3, CTLA-4, 2B4, and BLTA. Inhibition of these immunological checkpoints has shown outstanding capability of reversing the exhausted state, but its efficacy in clinical malignancy varies across different cancers. Also, these markers can be used to assess response to cancer therapy. The present chapter reviews the concept of T-cell exhaustion, exhaustion biomarkers, as well as the role of T-cell exhaustion in cancer immunopathology and therapy. Also, we discuss open questions and areas of further research in the field.