<p>Desmoplastic small round cell tumor (DSRCT) is an aggressive soft-tissue sarcoma driven by the EWSR1::WT1 fusion protein resulting from a chromosomal translocation between the EWSR1 (Ewing sarcoma breakpoint region 1) gene on chromosome 22 and the WT1 (Wilms tumor 1) gene on chromosome 11. This disease typically occurs in post-pubertal adolescent and young adult males, which suggests it may be hormonally driven through the androgen receptor (AR) pathway. Over the years, various groups have established a relationship between AR and DSRCT. Profiling studies have noted a high expression of AR in DSRCT. Fine et al. showed that combined androgen blockade led to a clinical benefit in three (all male) of six patients with stable disease or at least a minor response lasting three months. The AR pathway is relevant not only in prostate cancer but has been discovered to be oncogenic in salivary gland cancers, melanoma, and breast cancer. Though numerous AR-directed therapies are available to treat prostate cancer, AR has not been extensively evaluated as a therapeutic target in DSRCT. Preclinical studies revealed that AR stimulation increased cell proliferation. Conversely, single-agent targeting of the pathway delayed tumor growth in xenograft models. Pharmacodynamic analysis showed that AR inhibition activates the PI3K/Akt/mTOR pathway, and recent epigenetic analysis of AR binding showed that it may interact with EWSR1::WT1 and the forkhead protein family of transcription factors that regulate development and cellular differentiation. A deeper understanding of the impact of AR on the epigenetic landscape and signaling pathway crosstalk of DSRCT promises to expand the therapeutic arsenal of agents available to combat this deadly disease.</p>