It has been theorized that immune thrombocytopenia (ITP) is a syndrome characterized by various defects in immune regulation, resulting in a common phenotype, decreased blood platelets, and symptoms of mucocutaneous bleeding. Most often, successful treatment of the underlying connective tissue disorder with corticosteroids or other disease-modifying agents can simultaneously improve concurrent thrombocytopenia. The best evidence to date would support the targeting of treatment to the connective tissue disorder, expecting a simultaneous improvement in the platelet count. Due to the frequent relapses associated with many of the connective tissue disorders and the frequent use of immunosuppressant agents, splenectomy should be undertaken only in highly refractory patients. Differentiating the varying immunopathic etiologies that contribute to development of connective tissue disorders may lead to a better understanding of the mechanisms of thrombocytopenia in a subset of these patients. The use of target therapies to treat connective tissue disorders has the potential of reducing the risk of the development of ITP or, conversely, inducing the development of immune thrombocytopenia.