Biodegradable long-acting injectables are designed to remain at the injection site for an extended duration, resulting in prolonged local tissue reactions. It is crucial to assess and interpret these reactions in preclinical toxicity studies to identify any potential safety concerns for human use. However, evaluating the tolerability of these formulations poses challenges and there is limited published literature and a lack of specific regulatory guidelines. This chapter provides an overview of the pathophysiology of local tissue reactions associated with long-acting injectables and how these reactions are influenced by various properties of the formulation. It specifically focuses on the challenges of injecting long-acting injectables into confined spaces, using intraarticular administrations as an example. Finally, the chapter discusses several aspects which may need to be taken into consideration when determining the clinical relevance of preclinical findings and the local tolerability of long-acting injectables.