<p>Recent clinical trials have demonstrated the efficacy of different modalities of systemic therapy in treating brain metastases, including immune checkpoint inhibitors and various types of targeted therapy. These findings expand treatment options for these intracranial tumours, which are linked to significant morbidity and poor outcomes. Despite these advances, important challenges remain. These include the difficulty of identifying predictors of intracranial response to such therapies. The intracranial activity of anti-tumour agents is dependent on the complex interplay between the cellular components of the tumour microenvironment, consisting of both brain-resident cell types and peripheral immune cells. A deeper understanding of these interactions is essential for identifying mechanisms that contribute to inter- and intratumoural heterogeneity in treatment sensitivity. This review provides a comprehensive overview of the mechanisms by which the constituent cell types of the tumour microenvironment of brain metastases contribute to tumour progression and therapy resistance. Herein, a conceptual model of the relevant biological pathways is outlined along with references to how specific vulnerabilities could be utilised to develop more effective therapeutic strategies.</p>