Symptomatic splenomegaly, a frequent manifestation of myelofibrosis (MF), represents a therapeutic challenge. It is frequently accompanied by constitutional symptoms and by anemia or other cytopenias, which make treatment difficult, as the latter are often worsened by most current therapies. Cytoreductive treatment, usually hydroxyurea, is the first-line therapy, being effective in around 40% of the patients, although the effect is often short lived. The immunomodulatory drugs, such as thalidomide or lenalidomide, rarely show a substantial activity in reducing the splenomegaly. Splenectomy can be considered in patients refractory to drug treatment, but the procedure involves substantial morbidity as well as a certain mortality risk and, therefore, patient selection is important. For patients not eligible for splenectomy, transient relief of the symptoms can be obtained with local radiotherapy that, in turn, can induce severe and long-lasting cytopenias. Allogeneic hemopoietic stem cell transplantation is the only treatment with the potential for curing MF but, due to its associated morbidity and mortality, is usually restricted to a minority of patients with poor risk features. A new class of drugs, the JAK2 inhibitors, although also palliative, are promising in the splenomegaly of MF and will probably change the therapeutic algorithm of this disease.