Although Ewing sarcoma represents a rare malignancy of childhood and adolescence, it has attracted the attention of an increasing number of excellent researchers. With a tumor-specific EWS-ETS translocation coding for a transcription factor, which obviously profoundly modifies the intracellular signaling network, this rare malignancy opens insights in pathological gene and protein regulation. Despite decades of basic and translational research, clinical improvement has not yet been modulated by novel targeted therapies, but is produced by well-designed multimodal treatments. By using these multimodal treatment approaches, which always include chemotherapy and local treatment, the prognosis has been improved by up to 70%. For more than 10 years, the survival curves have plateaued at a relatively high level. However, a 30% relapse rate is still unacceptably high, considering that the prognosis after relapse is fatal for most patients. Therefore, novel treatment approaches are urgently required. This article provides an overview of the Ewing sarcoma research of the past few years; while not claiming to be complete, it offers a view on putative strategies with translational potential.