ONECUT gene family members of transcription factors (TFs) are documented for their DNA binding region's single-cut domain and homeodomain. The homeodomain of ONECUT has a dual role depending on the target gene, and their involvement in transcriptional activation [1], [2]The cut domain participates in both DNA binding and transcriptional activation. The cut domain of the ONECUT proteins contains a motif that interacts with several coactivators [3], [4]. ONECUT transcription factors are essential in the development of liver and pancreas [5]. ONECUT1 isreffered as Hepatocyte Nuclear Factor 6 (HNF6) or (HNF6-α) recognized as a functional ortholog of the mammalian ONECUT2 protein. ONECUT1 is an essential factor for both physiological and pathological functions in the liver and pancreas and is a major liver-enriched transcription factor that stimulates the transcription of liver-associated genes (HNF-4 and HNF-3β (FoxA2) and antagonizes glucocorticoid-stimulated gene transcription, namely 6-phosphofructo-2-kinase and phosphoenolpyruvate carboxykinase [6], [7], [8], [9]. Besides, ONECUT1 is a critical fate regulator involved in the development of pancreatic progenitors for later endocrine specification [10]. ONECUT1 regulates several cellular processes, including cell cycle regulation and glucose metabolism. ONECUT2, the second member of the ONECUT family is a highly conserved gene from drosophila to humans, also known as hepatocyte nuclear factor 6-beta (HNF-6-β). ONECUT2 binds to DNA independently or in cooperation with the homeodomain [1]. ONECUT2 play a significant role in regulating diverse biological processes, including cell differentiation, cell fate commitment, organ morphogenesis, cilium assembly, epithelial cell development, positive regulation of cell migration, regulation of cell-matrix adhesion, transcription by RNA pol II, and negative regulation of transforming growth factor (TGF). . ONECUT2 is highly expressed in the immune and nervous system, and in several organs such as gallbladder, small intestine, and hepatobiliary tissues [10], [11], [12]. Both ONECUT1 and ONECUT2 play an essential role in mammalian intrahepatic biliary system development [11]. ONECUT3 is the third member of the ONECUT family that plays an important role in cell differentiation and metabolism and ONECUT1 is the paralog of this ONECUT3 Besides the role of ONECUT family in oran development, aberrant expression of ONECUT transcription factors contributes to the development of several human diseases, including cancer. In the present review, we highlight the role of ONECUT family members and their associated pathways and targets during cancer progression in different experimental models. Further, we summarize the role of ONECUT proteins in various cellular functions including metastasis, cell cycle progression, stemness maintenance, and chemo-resistance.