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Simple Summary: In 2021, the identification of effective biomarkers became a major focus of prostate cancer (PCa) in order to improve outcomes and select potentially responsive patients. The aim of this contribution is to review the main 2021 novelties in prognostic and therapeutic markers in PCa, with special reference to PCa grading, aggressive variant PCa and molecular markers predicting significant disease or response to therapy. The 2021 novelties in prognostic and therapeutic tissue markers in patients with prostate cancer (PCa) can be subdivided into two major groups. The first group is related to prognostic markers based on morphological and immunohistochemical evaluations. The novelties in this group can then be subdivided into two subgroups, one involving morphologic evaluation only, i.e., PCa grading, and the other involving both morphologic and immunohistochemical evaluations, i.e., aggressive variant PCa (AVPCa). Grading concerns androgen-dependent PCa, while AVPCa represents a late phase in its natural history, when it becomes androgen-independent. The novelties of the other major group are related to molecular markers predicting significant disease or response to therapy. This group mainly includes novelties in the molecular evaluation of PCa in tissue material and liquid biopsies. [ABSTRACT FROM AUTHOR]