Ewing sarcoma (ES) is an aggressive pediatric bone tumor that is prone to metastasis. Due to low five-year survival rates and limited therapeutic options for metastatic disease, there is a dire clinical need for improved ES treatments. Targeting p21-activated kinases (PAKs) may be key. PAK1 and PAK4 are associated with aggressive ES and poor patient outcomes, although their molecular mechanisms remain largely uncharacterized in this disease. This commentary aims to highlight the recent advancements made to the understanding of PAK1 and PAK4 in ES in the paper "p21-activated kinases as viable therapeutic targets for the treatment of high-risk Ewing sarcoma" by Qasim et al.