Trabectedin is indicated for the treatment of advanced soft tissue sarcoma (STS) after failure of standard therapy with anthracyclines and ifosfamide, or as first-line therapy for patients who are unsuited to receive these agents. Since trabectedin first became available for clinical investigation in 1995, numerous retrospective analyses and Phase II studies have documented its activity and provided useful insights into its unique clinical profile. An extensive research program of randomized studies was subsequently undertaken to identify methods of optimizing the use of trabectedin in clinical practice. Some main areas of interest involved its use in the first-line setting, its use in combination regimens and its activity in specific sarcoma subtypes. In this article, clinical trial results are reviewed with the aim of continually refining trabectedin’s place in the therapy of advanced STS.