Despite being effective, and approved for the treatment of a wide range of tumours, targeted therapies are generally less effective against brain metastases. Now, research using mouse models of brain metastases confirms that the PI3K inhibitor buparlisib is effective against tumours located in mammary fat pads, but not against those located in the brain, despite the established ability of buparlisib to cross the blood–brain barrier. A high-throughput screening approach indicated that exposure to neuregulins, from the tumour microenvironment, resulted in the upregulation of HER3. The relevance of this finding to anticancer drug resistance was confirmed by the sensitization of brain metastases to buparlisib resulting from inhibition of HER3: mice treated with this combination had a substantial delay in the growth of brain metastases, and prolonged survival. These findings demonstrate the importance of the tumour microenvironment in determining tumour sensitivity or resistance to targeted therapies.