The classification systems for sarcomas are complex and the disease is rare and heterogeneous with over 50 subtypes making sarcoma diagnosis challenging even to the experienced pathologist. Cure rates in osteosarcoma improved to approximately 50% with incorporation of adjuvant chemotherapy in the 1980s. This also permitted limb-salvage operations which are now standard-of-care. But since then there has been a plateau in systemic treatment with a general poor response to conventional cytotoxics in sarcoma in general. At the same time, sarcoma provides a useful model for understanding mechanisms of tumorigenesis and drug resistance. MDM2 is a negative regulator of p53 tumour suppressor protein leading to its inactivation and is amplified in 50% of liposarcomas and in approximately 20-30% of soft tissues sarcoma as opposed to 7% of human cancers. Some pleomorphic variants also have mutations in TP53. Genomic alterations (mutations and copy number variations) in STS also include 18% myxoid/round cell with activating mutations in the PIK3CA gene. CDK4 is highly amplified in >90% of WDLPS and DDLPS. These findings provide “newer” potential molecular targets for sarcomas with potential candidates including MDM2 inhibitors (e.g. RG7112 – a small molecule preventing MDM2/p53 binding) and CDK4 inhibitors (e.g. Palbociclib, a potent oral inhibitor of CDK4/6 preventing downstream phosphorylation of retinoblastoma (RB) protein in liposarcomas). Others include inhibitors of the aurora kinase family comprising serine/threonine kinases which are essential components of the mitotic pathway. At present chemotherapy remains the standard for some advanced-stage and in metastatic STS and histological subtype impacts choice of treatment. For the future, conventional histopathology should be partnered with molecular pathology and genotyping which are critical in improving our understanding of disease and to allow us to aim for precision sarcoma therapy. Clinical trial designs should reflect our improved molecular knowledge of this heterogeneous group of diseases.