Biopharmaceuticals are important treatment options for a variety of chronic and sometimes life-threatening diseases. Compared with the traditional small molecule drugs, biopharmaceuticals have specific characteristics, which might also influence their safety profile. They have, for example, a complex production process, limited predictability of preclinical to clinical data, a high potential for immunogenicity, and adverse events can often be related to an exaggerated pharmacology. The limited predictability of preclinical to clinical data and the known limitations of randomized controlled trials results in limited knowledge of the safety profile of biopharmaceuticals at the point of their approval, underlining the need for pharmacovigilance. Due to their specific characteristics, pharmacovigilance activities required for biopharmaceuticals might differ from those required for small molecules. This review discusses characteristics and potential challenges with the pharmacovigilance and risk management of biopharmaceuticals as compared with small molecules, and proposes remedies for some of the emerging problems. Spontaneous reporting of adverse drug reactions (ADRs) is important in the detection of new, rare and/or serious ADRs. However, causality assessment remains complicated because of concomitant diseases or drugs. This is particularly the case with biopharmaceuticals, as they are often indicated to treat severe and/or life-threatening diseases in patients who often have other diseases and are treated with concomitant medication. Proactive risk management has been implemented in the EU by the obligatory submission of an EU risk management plan (EU-RMP). In this, the (potential) risks should be described and pharmacovigilance activities proposed. Pharmacovigilance activities can be either routine or additional (post-authorization safety studies [PASS]) activities. During safety assessment, stakeholders are encouraged to use knowledge obtained with biopharmaceuticals with a comparable pharmacology. PASS of biopharmaceuticals with a comparable pharmacology may therefore be used to complement each other. Since biopharmaceuticals are often used in a specialized hospital setting, it is expected that large population-based databases will contain limited information on biopharmaceuticals. Registries have therefore been shown to be an important tool to obtain pharmacovigilance data. Since small changes in the production and purification process might alter the safety profile, activities to improve traceability of the specific biopharmaceutical responsible for the ADR should be taken into account. Key messages in safety management of biopharmaceuticals remain: be prepared for the unexpected, be aware of confounding by disease (severity) and maintain exposure ascertainment/traceability throughout the logistical chain.