The detection of N-nitrosamine impurities in medicines and the recent emergence of nitrosamine drug substance related impurities (NDSRIs) has posed a great challenge to manufacturers of drug products and regulators alike. NDSRIs are primarily associated with reactions occurring in the drug product which brings particular complexity. This paper will explore the current technical knowledge surrounding the formation of these impurities, including the risk factors, reaction conditions, and potential mitigation strategies. Scientific understanding of these areas is still evolving, and we will highlight both the scientific progress made and discuss the significant gaps in mechanistic knowledge still remaining. These gaps render accurate predictions of NDSRI formation extremely challenging. The pharmaceutical industry should continue to work on potential mitigation strategies and generation of additional scientific data to address the mechanistic gaps. Regulatory guidance and policy will continue to advance and adapt in response to further changes in scientific understanding.