Brain metastasis, which commonly arises in patients with lung cancer, breast cancer and melanoma, is associated with poor survival outcomes and poses distinct clinical challenges. The brain microenvironment, with its unique cell types, anatomical structures, metabolic constraints and immune environment, differs drastically from microenvironments of extracranial lesions, imposing a distinct and profound selective pressure on tumour cells that, in turn, shapes the metastatic process and therapeutic responses. Accordingly, the study of brain metastasis could uncover new therapeutic targets and identify novel treatment approaches to address the unmet clinical need. Moreover, such efforts could provide insight into the biology of primary brain tumours, which face similar challenges to brain metastases of extracranial origin, and vice versa. However, the paucity of robust preclinical models of brain metastasis has severely limited such investigations, underscoring the importance of developing improved experimental models that holistically encompass the metastatic cascade and/or brain microenvironment. In this Viewpoint, we asked four leading experts to provide their opinions on these important aspects of brain metastasis biology and management.