Anemia is a major complication of chronic kidney disease (CKD), which is mainly caused by the impaired ability of erythropoietin (EPO) production. Hypoxia-inducible factor (HIF) has been demonstrated to regulate gene expression of erythropoietin and this process is mediated by prolyl hydroxylase domain (PHD) proteins. PHD inhibition can stabilize HIF. Therefore, various PHD inhibitors have been developed for the treatment of renal anemia. Recent clinical trials have shown the promising EPO production under using of PHD inhibitors as well as non-inferior effect for anemia correction in patients with or without dialysis compared to erythropoietin stimulating agents (ESAs) or placebo. Moreover, HIF is induced by hypoxia and HIF stabilization increases gene transcription by binding to hypoxia response elements (HREs), thus upregulating EPO and other genes, which leads to EPO production and pleotropic effects. These pleotropic effects include iron metabolism, metabolic change of glucose and lipid, fibrosis, inflammation, immune modulation, and cancer biology. Through these signaling pathways, several disease such as diabetic nephropathy, acute kidney injury, renal fibrosis, CKD progression, infection, and cancer development may be influenced by PHD inhibitors. In addition to the efficacy of PHD inhibitors, we also concern if there is any severe adverse effect such as cardiovascular risk or mortality would be induced by HIF-PHD pleotropic effect. Large size of patient number and longer study duration should be performed to evaluate these pleotropic effects.