The paradigm of surface-expressed programmed death ligand-1 (PD-L1) signalling to immune cell programmed death-1 (PD-1) to inhibit anti-tumor immunity has helped develop effective and revolutionary immune checkpoint immunotherapies using antibodies blocking these extracellular interactions. The recent discovery of tumor cellintrinsic PD-L1 signals has broadened understanding of pathologic consequences of PDL1 signals that now includes control of tumor growth and survival pathways, stemness, non-canonical immune effects, DNA damage responses, and significant gene expression regulation. These insights suggest that the prevailing surface-expressed PD-L1 signalling paradigm is important, but incomplete in important respects. This chapter discusses recent advances in understanding cell-intrinsic signals, mechanisms for signal controls and important immunopathologic consequences including resistance to cytotoxic agents, targeted small molecules and immunotherapies. Cell-intrinsic PD-L1 signals present novel drug discovery targets and potential for reliable treatment response biomarkers. PD-L1 is an immunoglobulin superfamily member. A potential class effect of cell-intrinsic tumor signals through other immunoglobulin superfamily members (e.g., PD-1) and cellintrinsic PD-L1 signals in non-tumor cells are discussed briefly as are non-canonical PDL1 signals from soluble and vesicle-bound PD-L1 and its isoforms and non-canonical antiPD-L1 effects. The chapter concludes with suggestions for addressing the most pressing challenges and opportunities in this rapidly developing field.