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ABSTRACT Introduction Indoleamine 2,3-dioxygenase 1 (IDO1) has been considered as an attractive intracellular target for the development of small-molecule cancer immunotherapy. Results in human clinical studies indicated that the first-generation IDO1 inhibitor epacadostat lacked anticancer activity when combined with the anti-PD-1 antibody pembrolizumab. Epacadostat inhibits IDO1 activity by forming a tertiary IDO1-heme-inhibitor complex. Recently, IDO1 inhibitors capable of displacing the heme group to form a binary high-affinity complex have been discovered and investigated in humans. Areas covered Structures, mode of action, preclinical activities, and status of clinical development are discussed and compared between the two classes of IDO1 inhibitors that bind to IDO1 protein in the presence (holo-IDO1) or absence (apo-IDO1) of the heme group, respectively. By selectively displacing the heme from IDO1 enzymes, apo-IDO1 inhibitors demonstrate high target selectivity, durable target engagement, and exceptional potency in cellular assays. Data from publications, patent disclosures, and conference proceedings as recent as 2019 are analyzed and summarized. Expert opinion The outcomes in cancer patients for the first-generation IDO1 inhibitors were disappointing. However, the unique mode of action by the heme-displacing IDO1 inhibitors might help their successful clinical translation and provide a novel class of anticancer drugs for cancer immunotherapy.