Myeloid sarcoma (MS) is a very rare disease in both adults and children. Prognosis is poor in adults; in the pediatric age, the prognostic impact of extramedullary disease is controversial. Systemic therapy represents the mainstay of treatment even in isolated MS, but a comparison between different induction regimens is very limited in the literature. To date, it is still not clear if induction treatment should differ from that of other acute myeloid leukemias and stem cell transplant is considered for consolidation in both leukemic patients and in those with isolated disease. Our study describes a retrospective series of 13 cases of MS (adults and children), diagnosed and treated at our institute over 18 years. We report the results of immunophenotypic, cytogenetic and molecular studies, therapeutic approaches, and outcome, in order to establish the best strategy for patients’ workup.