Soft tissue sarcoma (STS) represents a heterogeneous group of mesenchymal malignant tumors with variable natural history. This term was first introduced to describe a circumscribed neoplasm consisting of malignant fat cell occurring principally in the trunk (Abernethy, 1817). Nowadays, more than 30 types of STS have been described, and many of these present innumerable subtypes. Despite this wide range of entities, they represent less than 1% of all types of cancer, but still one of the most therapeutically challenging group of tumor (Choong & Rudiger, 2008). Surgery is the keystone of treatment, associated or not to adjuvant method, and the two aims are avoid metastatic spread and local relapse. Despite advances in local control of the sarcomas, the metastatic disease, which is the cause of death for most patients, presents little recent advances. In fact, 10% of patients have metastasis at the diagnosis and 25% with localized disease will develop distant spread (Delaney et al, 1991). The systemic disease occurs primarily by hematogenic spread, and the lungs are the most common distant organs involved by the distant metastasis. Some subtypes demonstrated predilection for lymphatic route of dissemination such as synovial sarcoma and epithelioid sarcoma while the alveolar sarcoma targets the brain involvement. In contrast to bone sarcomas, soft tissue malignancies do not respond well to chemotherapies schemes. This may be explained by the diversities of subgroups or by different factors that affect the prognosis. Therefore, the difficult in treating soft tissue sarcomas is determinate which patients will need the adjuvant chemotherapy or radiation therapy. The indication of these methods is guided by factors that predict the risk of metastatic disease or local recurrence. These factors are called prognostic factors and the purpose of this chapter is to define the different prognostic factors of soft tissue sarcoma. As a heterogeneous group, the behavior and natural evolution of this tumor are variable, but, in general aspects the metastatic spreading is observed in about one third of the patients, local relapse is seen in 10% to 30% and the global 5-year survival is 60%. Different factors are reported in the literature such as tumor grade, size, location, vascular invasion, histological necrosis and presence of cytogenetic markers. However, the importance of each factor is unclear. In this chapter we will discuss each prognostic factor including: age, sex, location, size, subtype, histological aspects, grade, surgical manipulation, recurrence, imunohistochemical pattern, genetic and gene markers.