Brain metastasis is a major cause of systemic cancer morbidity and mortality. Many factors participate in the development and maintenance of brain metastases. The survival of the metastasis depends upon crucial interactions between tumour cells and the brain microenvironment during its development at the new site. This review focuses on the pathobiological mechanisms involved in the establishment and regulation of brain metastases. Developments in molecular biology have vastly expanded our knowledge about the mechanisms of invasion, proliferation, metastatic cell signalling, and angiogenesis in brain metastases. Advances in this understanding of the pathobiology of brain metastasis may lead to novel targeted treatment paradigms and a better prognosis for patients with brain metastatic disease.