The treatment of relatively rare malignancies, such as those of the salivary glands and iodine refractory thyroid cancer, has been invigorated by the development of novel molecular targeting agents. Accrual to clinical trials for these disease sites continues to be limited by their relatively low incidence. Nonetheless, multicenter collaborations have contributed greatly to the development of a number of emerging systemic therapies. This article briefly summarizes the epidemiology and pathogenesis of salivary gland and thyroid cancer, and then describes some of the new drugs under evaluation for these malignancies.