Hereby we present a comprehensive assessment of the PD-L1 IHC diagnostic test in NSCLC at different levels: (1) a comparative cross-validation of the two more widely used antibodies, namely the Dako 22C3 and Ventana SP263 clones; (2) a description of clinical PD-L1 reflex testing in the first 564 cases in an accredited laboratory; (3) the concordance of PD-L1 overexpression by IHC versus PD-L1 upregulation by in situ RNA (RNA-ISH); and (4) the potential role of digital pathology in the automated scoring using open source available software (QuPath). The gene discussed is CD274; the disease is non-small cell lung carcinoma.