Sarcomas are different tumor entities of rare mesenchymal origin malignant neoplasms arising in bones and soft tissues and affecting both children and adults. Sarcomas are commonly identified in genetic cancer predisposition syndromes, such as Li-Fraumeni syndrome. Poor clinical outcomes are commonly described, being sarcoma-related metastatic disease predominantly detected in the lungs. There is a paucity of treatment options, requiring the screening of potential biomarkers and new treatment strategies to greatly improve this scenario. Chromosomal rearrangements resulting in gene fusions are the major characteristic hallmarks identified in sarcomas, and the cytogenetic analysis is the standard method used in the clinical practice to describe these neoplasms. Over the past decades, advances in molecular technologies for cytogenetic and genomic analyses have been gradually providing new molecular information about the biology of these neoplasms, which favors a better characterization of the molecular landscape of these rare and highly complex tumors. Therefore, other molecular alterations and candidate genes have been described as clinically relevant in sarcomas, which can aid in refining diagnosis, prognosis, and tumor classification and also guide novel targeted therapies. Additionally, liquid biopsy has emerged as a promising area of cancer investigation for detecting circulating biomarkers in body fluids and could provide additional molecular information on tumor dynamics and heterogeneity of bone and soft tissue tumors.