Clinical cancer genetics has traditionally focussed on subsets of cancers; rare, dominant pedigrees; and limited genomic capacity. Recent genomic advances promise to transform this view of cancer. Sarcomas are a rare group of cancers with the hallmarks of strong genetic susceptibility. The ISKS, an Australian-led, international consortium, has recruited from sarcoma clinics >1,400 families affected by sarcomas. This young population (median 48 years) has a high rate of multiple cancer cases (17%), and an excess burden of cancer in first-degree relatives (FDR). Blinded pedigree analysis identified recognizable cancer syndromes in 29% of the cohort. We conducted a targeted exon screen for 74 known cancer risk genes in 782 ISKS cases, and 235 matched controls. Additional controls were obtained from the Lifepool consortium (2010), and the European American EVS dataset (4300). In total, pathogenic variants were observed in 58% of ISKS cases, more than controls (P<0.0001). Individuals carrying pathogenic variants had an earlier age of first cancer onset (AFCO) than those who did not (43 versus 51y; P<0.001). 179 individuals (22.8%) carried >1 variant (compared to 12.8% of controls (P=0.001), correlating with earlier AFCO (Log Rank for trend, P=0.001). The AFCO was younger for individuals carrying 3+ variants (36y) than for TP53 mutations in TP53 (40y), but the rate of cancer in FDR was lower (0.098±0.025 versus 0.185±0.024, P=0.037), consistent with polygenic risk transmission. Gene-wise analysis identified 6 genes with an excess burden of pathogenic variation (in order of enrichment): ATR (P<0.0001, Benjamini-Hochberg corrected), TP53 (P<0.0001), MLH1 (P=0.005), ERCC2 (P=0.005), BRCA2 (P=0.04), and NF1 (P=0.04). Variants in ERCC2 were associated with genomically simple sarcomas, while complex genotypes were associated with variants in TP53, ATR and BRCA2. Notably, radiation is the strongest known environmental risk factor for sarcomas. In summary, this landmark study has identified known and previously unsuspected genetic drivers in more than half of the sarcoma population, with immediate implications for clinical care.