Patients having malignant pheochromocytomas and paragangliomas traditionally have been treated with systemic chemotherapy and (131)I-meta-iodobenzylguanidine. However, these therapies have limited efficacy and the potential for significant toxicity. Over the last decade, researchers have discovered new gene mutations associated with malignant pheochromocytomas and paragangliomas, facilitating a better understanding of the molecular pathways involved in the development of these tumors. This new knowledge has brought with it the potential to test new medications that specifically target the signal transduction abnormalities known to be involved in malignant transformation. We are among the groups to have recently reported the use of the tyrosine kinase inhibitor sunitinib in a limited number of patients with malignant pheochromocytomas and paragangliomas. The use of sunitinib was associated with a reduction in the size of the tumors, their biochemical markers, and symptomatic improvement. In this review, we will explore these newly understood molecular pathways and the emerging therapies that may change the management of this disease.