Safety margins and exposure margins derived from nonclinical toxicology studies are critical components in the risk assessment and progression of drug candidates through clinical development. These margins, typically calculated by comparing the no-observed-adverse-effect level (NOAEL) from animal studies to anticipated and/or measured human exposures, provide a framework for understanding the potential for adverse effects in humans. Importantly, the minimum expected margins are not universal and can vary significantly depending on the route of administration, intended clinical indication, and clinical stage. Biotherapeutics administered intravenously, for example, result in different systemic exposures and toxicological profiles compared to local routes, such as ophthalmic or inhalation. Similarly, acceptable safety or exposure margins may be narrower or even absent in advanced cancer indications, where higher risk levels are tolerated to gain potential clinical benefit. This risk tolerance contrasts with autoimmune or pediatric indications, for which a higher safety threshold is required. Recognizing these differences is essential for appropriate study design, regulatory interactions, and risk-benefit evaluations throughout the drug development process. Anonymous case studies highlighting these differences will be presented for various biopharmaceuticals.