Dopamine agonists are usually very effective in the treatment of prolactinomas. Nonetheless, a subset of individuals does not respond satisfactorily to these agents, and this resistance is characterized by failure to achieve normoprolactinemia and a 30% or more reduction in maximal tumor diameter (in the case of macroprolactinoma) under maximally tolerated doses. The overall prevalence of dopamine agonist resistance is 20–30% for bromocriptine (BRC) and around 10% for cabergoline (CAB). The 2 main predictive factors are male gender and tumor invasiveness. The management of drug-resistant prolactinomas includes several options. Any BRC-resistant patient should be switched to CAB which will normalize prolactin in 80% of patients. As long as adverse effects do not develop, dose escalation of CAB is reasonable, with the expectation that subsequent dose reduction will be possible. Echocardiographic monitoring is advised in such patients because of the potential association with cardiac valvular fibrosis. Also, maintaining maximal CAB doses at 3.5 mg/week may lead to progressive hormonal control in a significant proportion of patients. Complete resistance to CAB is infrequent. In a study of 122 patients with a macroprolactinoma, only 7 (6%) could not achieve control despite maximal CAB doses for > 12 months. A large resistant prolactinoma is also an indication for transsphenoidal neurosurgery, aiming at a debulking which may improve postoperative medical control. For patients who harbor aggressive prolactinomas, radiotherapy may be considered. However, normal prolactinemia will eventually occur in only one-third of patients after many years. Finally, temozolomide may be a therapeutic option in malignant/aggressive prolactinomas.