 Biliary tract cancers, namely cholangiocarcinomas and gallbladder cancers, have among the poorest prognoses of any cancers, with fewer than 10% of patients surviving for five years after diagnosis. One of the reasons for this very poor outlook is that so little is understood about the biology of biliary tract cancers. Not knowing what genes drive the development of these cancers makes both early detection and treatment very difficult. As a result, there are currently no targeted molecular therapies for cholangiocarcinomas or gallbladder cancer, even though these cancers are becoming more common worldwide. To improve this grim clinical situation, researchers examined the genome sequences of 239 biliary tract cancer samples and their surrounding normal tissues, and the gene expression profiles of 160 samples. They identified several distinct genetic profiles, that is, characteristic sets of mutations or expression patterns, that correlated with the tumor location within the bile duct and with patient survival. For example, mutations in ELF3, a gene newly characterized here as a tumor suppressor, were unique to cancers originating outside the liver, and a portion of these cancers had a relatively better prognosis. In contrast, gallbladder cancers more frequently had greater numbers of accumulated mutations and a poorer prognosis. The researchers also discovered a distinct hypermutated group that was associated with very poor prognosis, but could likely be targeted by antibody-based therapies. Many of the identified mutations occurred in genes related to cell growth and division that were not previously known to be involved in biliary tract cancers or, in a few cases, were not previously known in any type of cancer. Other mutations occurred in genes that themselves regulate the expression of whole suites of genes and, therefore, have an outsize effect on cell behavior. Numerous samples, including some with the worst prognosis, expressed high levels of molecules that help the tumors evade the immune system. This tumor defense system has been successfully targeted to treat other cancers. In all, approximately 40% of the samples studied had some feature that could be targeted by drugs currently used to treat other cancers. These findings should thus spur major advances in biliary tract cancer diagnostics and therapy.