In the past years, immunotherapy emerged as a novel modality of clinical oncology. The development and introduction of immune checkpoint inhibitors required the development of companion diagnostics, the PD-L1 protein immunohistochemical tests. Unfortunately, almost all checkpoint inhibitors were exclusively validated by a specific PD-L1 in vitro diagnostic test with its own evaluation protocol. These tests have different diagnostic sensitivity for PD-L1 protein and the evaluation protocols differ in many respects, as cancer and immune cell positivities are considered variously in the immunotherapy-specific evaluation schemes. Accordingly, in the routine PD-L1 diagnostics, it is crucial to follow the individual therapy-specific technical and evaluation protocols since these are not interchangeable and non-adherence may affect therapeutic efficacy.