Insulin is a therapeutically relevant molecule with use in treating diabetes patients. Unfortunately, it undergoes a range of untoward and often unpredictable physical transformations due to alterations in its biochemical environment, including pH, ionic strength, temperature, agitation, and exposure to hydrophobic surfaces. The transformations are prevalent in its physiologically active monomeric form, while the zinc cationcoordinated hexamer, although physiologically inactive, is stable and less susceptible to fibrillation. The resultant molecular reconfiguration, including unfolding, misfolding, and hydrophobic interactions, often results in agglomeration, amyloid fibrillogenesis, and precipitation. As a result, a part of the dose is lost, causing a compromised therapeutic efficacy. Besides, the amyloid fibrils form insoluble deposits, trigger immunologic reactions, and harbor cytotoxic potential. The physical transformations also hold back a successful translation of non-parenteral insulin formulations, in addition to challenges related to encapsulation, chemical modification, purification, storage, and dosing. This review revisits the mechanisms and challenges that drive such physical transformations in insulin, with an emphasis on the observed amyloid fibrillation, and presents a critique of the current amelioration strategies before prioritizing some future research objectives.