Background: Myxofibrosarcoma (MFS) is among the most highly complex sarcoma types. Molecular cytogenetic studies have identified a high level of genomic complexity. Summary: This review provides an update of the current research related to MFS, with particular emphasis on emerging mechanisms of tumorigenesis and their potential therapeutic impact. Many novel possible molecular markers have been identified, not only for prognostication in MFS, but also to serve as possible therapeutic targets, and thereby improve clinical outcomes. However, the molecular pathogenesis of MFS remains incompletely understood. Key Messages: Patients suffering from advanced MFS might benefit from expanded molecular evaluation in order to detect specific expression profiles and identify drug-able targets. Moreover, immunotherapy represents an intriguingly perspective due to the presence of “T-cell inflamed” tumor microenvironment.