Rare diseases cumulatively affect more than 400 million individuals globally, frequently causing severe disabilities and creating a double burden on both the affected individuals and the healthcare systems. While genomic medicine has advanced in leaps and bounds, diagnosis and management of rare diseases continue to be a herculean challenge because of their heterogeneity and low prevalence and health system barriers. This entry elaborates on the intersection of rare diseases with disabilities, highlighting the medical, psychosocial, and economic burdens they create. The diagnostic odyssey for patients with rare diseases is typically long, and most have experienced years of misdiagnoses and ineffective therapies prior to achieving a firm diagnosis. Although technologies such as whole-exome sequencing and whole-genome sequencing (WGS) have enhanced the diagnostic yield, a considerable proportion of patients are still undiagnosed. New technologies such as long-read WGS and transcriptome sequencing offer a possible path forward to enhance diagnosis rates, even though challenges remain with variant interpretation and access to healthcare. Apart from medical complications, rare diseases also have significant psychosocial implications. Emotional suffering, isolation, and financial burden are borne by patients and caregivers because of the few treatments and lack of support systems. The financial burden of rare diseases is also considerable, with significant healthcare expenditure, productivity loss, and unequal treatment access widening inequalities. The absence of standardized approaches to measure rare disease burden, e.g., disability-adjusted life years (DALYs), also restricts resource allocation and policy decision-making. They need to be tackled by increasing the number of diagnostic techniques, coupled with better healthcare coordination, along with policy reforms for equitable access to diagnosis and treatment. By recognizing rare diseases as one of the significant contributors to disability and adopting multimodal approaches, health systems can help reduce the diagnostic odyssey, enhance patient outcomes, and lessen the burden on society due to rare diseases.