Simple Summary The PD-1/PD-L1 axis is not only involved in anti-tumour immune evasion of germinal center (GC)-derived diffuse large B cell lymphomas (DLBCL), but also inherently in the fine-tuned regulation of normal GC reactions during humoral immune responses. This checkpoint axis modulates crosstalks between B and T cells that allow positive selection for survival and proliferation. Malignant DLBCL cells may deceive and take advantage of these mechanisms to establish an immunosuppressive microenvironment. This review delves into PD-1/PD-L1 role in the complex inter-cellular interactions from normal GC reactions to DLBCL progression, in order to highlight vulnerabilities that could be targeted by promising combination immunotherapies. Besides a recognized role of PD-1/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells (T-FH) and regulatory T (T-FR) or B (Breg) cells are involved in positive selection of GC B cells and may result critical in the lymphoma microenvironment. Here, we discuss a role of PD-1/PD-L1 during tumour evolution in diffuse large B cell lymphoma (DLBCL), a paradigm of GC-derived lymphomagenesis. We depict a progression model, in two phases, where malignant B cells take advantage of positive selection signals derived from correct antigen-presentation and PD-1/PD-L1 inter-cellular crosstalks to survive and initiate tumour expansion. Later, a constant pressure for the accumulation of genetic/epigenetic alterations facilitates that DLBCL cells exhibit higher PD-L1 levels and capacity to secrete IL-10, resembling Breg-like features. As a result, a complex immunosuppressive microenvironment is established where DLBCL cells sustain proliferation and survival by impairing regulatory control of T-FR cells and limiting IL-21-mediated anti-tumour functions of T-FH cells and maximize the use of PD-1/PD-L1 signaling to escape from CD8(+) cytotoxic activity. Integration of these molecular and cellular addictions into a framework may contribute to the better understanding of the lymphoma microenvironment and contribute to the rationale for novel PD-1/PD-L1-based combinational immunotherapies in DLBCL.