Desmoplastic small round cell tumour (DSRCT) is an ultra-rare soft tissue sarcoma that is characterised by aggressive disease and dismal patient outcomes. Despite multi-modal therapy, prognosis remains poor and there are currently no effective targeted therapies available for patients with this disease. Advances in comprehensive molecular profiling approaches including next generation sequencing and proteomics hold the promise of identifying new therapeutic targets and biomarkers. In this review, we provide an overview of the current status of molecular profiling studies in DSRCT patient specimens and cell lines, highlighting the key genomic, epigenetic and proteomic findings that have contributed to our biological knowledge base of this recalcitrant disease. In-depth analysis of these molecular profiles has led to the identification of promising novel and repurposed candidate therapies that are suitable for translation into clinical trials. We further provide a perspective on how future integrated studies including proteogenomics could further enrich our understanding of this ultra-rare entity and deliver progress that will ultimately impact the outcomes of patients with DSRCT.