Sarcomas are rare, heterogeneous cancers with a mean age at onset that is earlier than that of many other types of cancer; however, the genetic basis of sarcoma remains largely unknown. Data from a recently published genetic-association study involving 1,162 patients with sarcoma from four different clinical study cohorts reveal that 55% of these patients have underlying monogenic or polygenic genetic variations that are either known to be or are likely to be pathogenic relative to their wild-type variants. Mutations in the known oncogenes TP53, ATM, ATR and BRCA2 were observed in patients with sarcoma, in addition to a surprisingly high prevalence of mutations in the gene that encodes ERCC2, a transcription factor required for nucleotide excision repair. A correlation was observed between earlier age at diagnosis and the presence of multiple pathogenic variants. These data demonstrate that, to some extent, sarcoma has a genetic aetiology.