The significance of epigenetics and precision medicine in the context of uncommon cancers, referred to as “rare cancers,” is investigated in this chapter. A comprehensive review of the current literature on noncoding RNAs (ncRNAs), natural products, and clinical trials specific to uncommon cancers was conducted. The role of ncRNAs in tumor biology is elaborated, revealing their dual influence on tumor suppression and oncogenesis, alongside current therapeutic strategies targeting these molecules. Recent clinical trial outcomes were analyzed to assess therapeutic potentials and innovations. The role of epigenetic mechanisms in rare cancer development and treatment, particularly focusing on how natural products can modify epigenetic mechanisms, such as DNA methylation, histone modifications, and the regulation of ncRNAs, was discussed in detail. The chapter emphasizes the potential of these natural products as therapeutic agents, or “epi-drugs,” in cancer prevention and treatment.