Melanoma, a severe type of skin cancer, poses significant management challenges due to its resistance to available treatments. Despite this obstacle, the high immunogenicity of melanoma renders it amenable to immune therapy, and NK cells have been identified as possessing anti-tumor properties in immunotherapy. The development of chimeric antigen receptor (CAR)-modified NK cells, or CAR-NK cells, has shown potential in enhancing immunotherapeutic regimens. To achieve this, researchers have explored various sources of NK cells, including those derived from the placenta, which offers benefits compared to other sources due to their limited ex vivo expansion potential. Recent studies have indicated the capacity to expand functional NK cells from placenta-derived cells in vitro that possess anti-tumor cytolytic properties. This chapter discusses the isolation of full-term human placenta-derived NK cells using Good Manufacturing Practice-based methods for CAR-NK cell therapy in melanoma.