Chordoma is an exceedingly rare tumor, marked by a slow growth rate. Surgery is the treatment of choice, but the most frequent sites of origin (spine and skull base) make treatment of primary disease challenging. Local relapses affect more than 50% of cases, with a minority of patients being cured by further surgery. Furthermore, metastases occur in at least 20% of patients. For residual or recurrent disease, high-dose radiation therapy may be indicated. Radiation therapy is currently the preferred local treatment when surgery is problematic, exploiting most recent techniques, including proton beams and carbon ions. However, systemic therapy is needed in patients non-amenable to surgery and/or radiation therapy. We reviewed systemic treatments currently available, and targets possibly druggable in the future in this orphan disease.