The availability of high-throughput sequencing techniques has made it possible to broaden the spectrum of uterine mesenchymal tumors and diagnose tumors that were previously unidentifiable using traditional histological tools alone. Fluorescence in situ hybridization (FISH) was a pioneer in the detection of diagnostic chromosomal rearrangements in uterine sarcomas. However, due to its limitations, it is increasingly being abandoned in favor of targeted or total RNA sequencing techniques, which allow the identification of cryptic rearrangements of partner genes. Identifying the “driver” chromosomal alteration (fusion or mutation) is diagnostic in single-genomic sarcomas, where a single alteration present in most tumor cells is at the origin of the oncogene. Analysis of the genomic profile reveals the tumor’s genomic complexity and can help the pathologist determine its benign or malignant nature in the appropriate clinicopathological context and predict the risk of progression of the disease. DNA sequencing, using multigene panels, exome sequencing, or, less reliably, RNAseq, can identify mutations that can support diagnosis or guide therapeutic strategy (targetable mutations). Herein, we illustrate the most critical techniques for the diagnosis of uterine mesenchymal tumors.