Umbilical cord blood (CB)-derived hematopoietic stem and progenitor cells (HSPCs) hold immense potential for regenerative medicine, particularly in hematologic malignancies and immune disorders. CB offers several advantages, including easy collection and reduced risk of graft-versus-host disease compared to other sources, like bone marrow. However, the clinical application of CB is often limited due to the relatively small number of HSPCs present in CB grafts, which can be insufficient for adult patients. This limitation has prompted researchers to explore various methods to expand HSPCs ex vivo. As research continues to refine expansion techniques, the future of CB HSPC therapy appears increasingly promising, offering new hope for patients requiring stem cell transplantation. Approaches to HSPC expansion include the use of cytokines, small molecules, epigenetic modulators, and advanced culture systems that mimic the bone marrow niche as well as emerging techniques such as gene editing. Of the key CB HSPC expansion methodologies, the use of epigenetic modifiers is among the most promising strategies for inducing proliferation while maintaining the stemness of CB HSPC. This section summarizes key methodologies for CB HSPC expansion and their transformative impact on clinical practice while providing a validated protocol for ex vivo expansion of CB-derived HSPCs using valproic acid and/or nicotinamide.