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The rapid expansion of biologic therapies for immune-mediated inflammatory diseases has raised significant clinical concerns regarding malignancy risk, particularly for patients with a history of cancer. This narrative review explores the safety of targeted therapies across dermatology, rheumatology, respiratory medicine, and gastroenterology to guide clinicians in these therapeutic dilemmas. We conducted a non-systematic review of the literature, prioritising longitudinal registry and real-world cohort data over clinical trials to better capture malignancy outcomes with long latency periods. Results indicate that tumour necrosis factor (TNF) inhibitors, which have the most extensive evidence base, do not consistently demonstrate an increased risk of overall incident malignancy or recurrence across specialties. Newer agents, including interleukin (IL)-17 and IL-23 inhibitors, show reassuring safety profiles in both trial and registry data. While dupilumab is associated with the potential diagnostic 'unmasking' of pre-existing cutaneous T-cell lymphoma, overall cancer rates remain stable among users. Most clinical guidelines support an individualised, multidisciplinary approach involving oncology consultation. We conclude that biologic agents can be used cautiously in certain patients with a history of malignancy following multidisciplinary discussion; however, in those with active malignancy there are no meaningful data that exist. Most evidence is heterogenous and excludes patients with a history of malignancy. Future management requires validated decision frameworks and mandatory participation in real-world patient co-created registries which leverage developing artificial intelligence tools to refine long-term safety assessments.