Abstract: Tumor cells can metabolize glucose through glycolysis to intermediates for biomacromolecule synthesis by inhibiting the activity of the pyruvate dehydrogenase complex (PDC) in mitochondria. In this process, pyruvate dehydrogenase kinases (PDKs) play a key role. The inhibition of the activity of PDKs can effectively block this metabolic pathway, activate mitochondrial oxidative metabolism, and induce tumor cell apoptosis. PDK inhibitors have become a research hotspot in medicinal chemistry, and novel structures targeting classical binding sites have been synthesized. In this paper, recent research progress on PDK inhibitors is reviewed to provide information on these latest entities and to explore their clinical applicability.