<p>The interchangeability of bioimilars (off-patent biologics) is a topic of ongoing debate in the literature. In the US, the FDA requires a demonstration of interchangeability before biosimilars can be interchanged on the market. However, this requirement is not mandated in other regions. Conversely, a joint statement from the Head of Medicines Agency and the EMA declared that once a biosimilar is approved in the EU it is interchangeable without the need for additional systematic switch studies to support the interchangeability at the prescriber level. The term interchangeability has a different meanings, depending on the country. To ensure the best interchange practice, a global definition of interchangeability is needed. Should biosimilars demonstrate both similarity to and interchangeability with the reference product before substitution or it is a matter of confidence of the healthcare professional, which can be attained through self-practice and available data from already switched patients? Would the recent calls and existing guidelines for using real-world data to support regulatory and clinical decisions be adequate for such interchangeable designation? In this review, we'll draw insights from the interchangeability of off-patent medicines (generics), and highlight the unique characteristics of biosimilars that differentiate them from generics affecting their interchangeability. We will highlight some regulatory standpoints and discuss clinical practices related to this practice. We will shed light on the procedures covered by this umbrella term, like switching and substitution, discuss the potential risks associated with the interchangeability of biosimilars, and suggest strategies to handle uncertainties from interchangeability practice.</p>