Less than 40% of patients with newly diagnosed adult immune thrombocytopenia will show spontaneous recovery within 12 months. Therefore, second-line treatments are frequently used to maintain a hemostatic platelet count or at best to cure the disease, with as few adverse effects as possible. Nevertheless, we lack head-to-head comparison studies of the different available treatments. Moreover, physicians have no robust predictors of response to guide decision-making on an individual basis. Therefore, there is no consensus, and decisions when to treat and with which drug must be individualized and shared with the patient based on factors related to the patient and the available second-line treatments. The main treatments used, based on their good benefit-risk ratio, are splenectomy, rituximab, and thrombopoietin-receptor agonists, but their prescription should be avoided in some situations and can be limited due to cost or to health authorities' restrictions on funding the last two drugs. This review presents the various second-line treatments used in primary persistent or chronic immune thrombocytopenia in adults and discusses their prescription in general and specific situations.