Purpose of review <p>Different regulatory frameworks regulate the development and approval of orphan drugs, which target rare diseases affecting small patient populations, across various countries. The global market for orphan drugs is projected to grow at a Compound Annual Growth Rate (CAGR) of 12.3% from 2019 to 2024. However, pricing and access to orphan drugs vary widely based on the regulatory incentives such as reimbursement policies, tax credits, market exclusivities etc. highlighting the disparities in treatment availability. Current study provides comparative analysis of regulatory frameworks for orphan drugs in six regions, viz., United States, European Union, Japan, Australia, Canada and India with the aim to identify the existing similarities and differences. Among the studied territories, only India has a semi-regulated market and others are well developed, evolved regulated markets.</p> Recent findings <p>The current review highlights discrepancies in financial as well as non-financial incentives offered, not only for the semi-regulated market, but also among the compared regulated markets. Therefore, present overview advocates the need for global harmonization and cohesive guidelines for orphan drug approvals.</p> Summary <p>The methodology of the article includes review of published articles and regulatory guidance documents for comparing orphan drug regulations, incentives and approval processes in each of the regions under the study. Current review is structured to elaborately discuss country-wise regulatory details for the territories under consideration. Overall, this comparative perspective underscores the need for global harmonization of orphan drug policies to encourage innovation while ensuring patient access to critical therapies. Understanding regulatory landscapes through uniform, cohesive guidelines can mentor pharmaceutical companies in navigating the complexities of orphan drug development.</p> Graphical Abstract <p></p>