The hallmark of Ewing's sarcoma (EWS) is a 
translocation--t(11;22)(q24;q12)--that most frequently results in the EWS/FLI1 
aberrant chimeric gene. Because EWS afflicts young patients, it stands out among 
the diverse sarcoma subtypes. The frontline, standard-of-care cytotoxic 
chemotherapy regimens produce minimal benefit in patients with metastases at 
presentation or those with relapsed disease. While the outcomes of 
chemorefractory EWS patients are generally poor, recent developments have led to 
the promising use of targeted therapy. Specifically, inhibition of insulin-like 
growth factor 1 receptor (IGF1R) signaling and the mammalian target of rapamycin 
(mTOR) pathways has emerged as a targeted therapy in EWS, with select patients 
experiencing dramatic therapeutic responses. However, targeted therapies in 
general, and these responders in particular, are faced with the ultimate 
conundrum of eventual resistance. To optimize response, combining IGF1R and mTOR 
inhibitor-based regimens with chemotherapy in the upfront setting in newly 
diagnosed high-risk EWS may clarify the true benefit of IGF1R inhibitors in 
these patients. Another option is to explore novel targeted multikinase 
inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors, which have 
experienced a surge in supporting preclinical data. Drugs inhibiting the 
downstream targets of EWS/FLI1 are also in preclinical development. However, 
ultimately, the underlying biomarker correlates of resistance and response must 
be delineated along with ways to overcome them. Novel agents, together with 
integration of advances in multimodal approaches (including surgery and 
radiation), as well as offering targeted therapies early in the disease course 
represent new strategies for confronting the challenges of EWS.