Systemic treatments are indicated for progressing or symptomatic metastatic pheochromocytoma or paraganglioma (mPPGL). Half of the patients with mPPGL have stable disease at 1 year and 9% do not progress at 5 years without any intervention; therefore, it is important to realize that a wait-and-see policy might be a better option in asymptomatic patients even when metastatic. On the other hand, rare cases progress rapidly and show aggressive malignant behavior. Chemotherapy, targeted therapy and immunotherapy are the treatment options available so far. The value of adjuvant systemic therapy after surgery for patients with stage II or III disease is unknown. Neoadjuvant treatment has not been studied prospectively; nevertheless, some patients with initially unresectable primary tumors have benefited from chemotherapy. This chapter explores the currently available treatments and most promising clinical trials for mPPGL.