Ewing sarcoma family tumors (EWS), which include classic Ewing's sarcoma in addition to primitive neuroectodermal tumor and Askin tumor, are the second most common variety of primary bone cancer to afflict adolescents and young adults. Multi-disciplinary care incorporating advances in diagnosis, surgery, chemotherapy, and radiation has substantially improved the survival rate of patients with localized Ewing sarcoma to nearly 70%. Unfortunately, those advances have not significantly changed the long-term outcome for those with metastatic or recurrent disease; 5-year survival remains less than 25%. This apparent therapeutic plateau exists despite extensive effort during the last four decades to optimize the efficacy of cytotoxic chemotherapy through combination of chemotherapies of mechanistically diverse action, dose-dense scheduling (provided as frequently as every 2 weeks), increased adjuvant treatment duration, and higher dosage per cycle (facilitated with parallel strides in supportive care incorporating growth factors). As has already occurred for malignancies such as breast or colon cancer, the "-omics-based" revolution has enhanced our understanding of the molecular changes responsible for Ewing's tumor formation and identified a number of potential targets (such as IGF-1R or mTOR) amenable to biological therapy. It has also created both a challenge and an opportunity to develop predictive biomarkers capable of selecting patients most likely to benefit from targeted therapy. In this review, we discuss current standard-of-care for patients with Ewing's sarcoma and highlight the most promising experimental therapies in early-phase clinical trials.