Brain metastases (BM) are an increasing challenge in the management of patients with advanced cancer. Treatment options for BM are limited and mainly focus on the application of local therapies. Systemic therapies including targeted therapies are only poorly investigated, as patients with BM were frequently excluded from clinical trials. Several targeted therapies have shown promising activity in patients with BM. In the present review we discuss existing and emerging targeted therapies for the most frequent BM primary tumor types. We focus on challenges in the conduction of clinical trials on targeted therapies in BM patients such as patient selection, combination with radiotherapy, the obstacles of the blood–brain barrier and the definition of study end points.