This chapter explores the global disparities in rare disease research and drug development, highlighting that over 90% of efforts are concentrated in less than 10% of the world’s population, primarily in the US and EU. Despite significant progress with over 1100 FDA-approved orphan drugs, 95% of rare diseases still lack approved treatments. The unique challenges in rare disease research are discussed, including limited scientific literature, small patient populations, and difficulties in patient identification. The critical role of patient registries and natural history studies in understanding disease progression and designing clinical trials is emphasized. The chapter examines the impact of the Human Genome Project on rare disease diagnosis and treatment, alongside emerging treatment modalities like gene therapy and innovative approaches using CRISPR and mRNA technologies. It addresses the potential and pitfalls of AI and machine learning in rare disease research, highlighting the risk of bias due to limited global data representation. The stark inequality in clinical trial distribution is noted, with over 80% of active rare disease trials concentrated in the US and EU. The urgent need for unified, patient-centric research platforms and strategies to bridge the global divide in rare disease research and drug development is underscored, calling for more inclusive approaches to ensure equitable progress in this critical field. This chapter also focuses on an overview of Chemistry, Manufacturing, and Controls (CMC) and its critical role in drug development for all modalities (small molecules, biologics, oligonucleotides, and gene therapy) with a focus on rare disease. The key elements of CMC requirements in regulatory dossier submission and approval are highlighted along with the latest trends of using AI in CMC.