Soft tissue sarcomas are a large group of heterogenous neoplasms, many of them are highly aggressive. Most of the cases are sporadic, without any well-defined pathogenetic factor. Potential risk factors are ionizing radiation, lymphatic oedema (secondary angiosarcoma of the breast), viral infections (HHV8 and Kaposi sarcoma), exposure to chemical factors (vinyl chloride and hepatic angiosarcoma). Genetic susceptibility plays a role in a minority of cases. However, mutations in TP53, ATM and ATR genes are associated with enhanced susceptibility to radiation. Li-Fraumeni syndrome (autosomal dominant TP53 mutation) predisposes to development of malignancies, one third of them are sarcomas. Genetic alterations observed in sarcomas could be divided into three major groups characterized by: (1) chromosome translocations; (2) simple karyotype and mutations; (3) variably complex karyotypes. A large part of sarcomas belong to the first group and the specific chromosal translocations could be utilized in the diagnostic process. A smaller number of sarcomas could be assigned to the second group, e.g. desmoid fibromatosis (CTNNB1 or APC mutations) and GIST (KIT, PDGFRA, or less frequently BRAF, SDH, NF1). A large number of sarcomas are characterized by complex and variable karyotypes. Gene copy number alterations are frequent in this group, e.g. in well-differentiated liposarcoma there is an amplification of MDM2, CDK4 and HMGA2 genes or sarcoma-specific chromosomal break regions present in the CHOP gene in myxoid liposarcoma and FKHR in alveolar rhabdomyosarcoma.