Off-label or unlicensed medicines use is extremely common in obstetric and paediatric clinical practice and necessitates greater emphasis on the underlying evidence of a medicines safety or efficacy. This creates significant challenges for pharmacists relating to the supply and use of medicines in this setting. Understanding how and why unlicensed or off-label medicine use occurs, together with the underlying evidence base, is critical for supporting the quality use of medicines. Addressing issues surrounding unlicensed or off-label medicine use in a collaborative manner with prescribers and patients can help reduce unnecessary patient concern, possible non-adherence and risk of suboptimal treatment outcomes. This review summarises current evidence and challenges surrounding off-label and unlicensed medicine use in the obstetric and paediatric clinical setting from the perspective of key stakeholders. It aims to support pharmacists in their evaluation of the appropriateness of off-label and unlicensed medicine use, and provide strategies to help manage these challenging medicines management decisions.