Backseat drivers take the wheel.

Somatic mutations in human cancers are comprised of those that contribute to the oncogenic phenotype, driver mutations, and those that reflect the general patterns of exposure and disrepair but are otherwise noncontributory, passenger mutations. Distinguishing drivers that can be of low frequency in any given tumor type from often more numerous passengers is a key challenge. In this issue of Cancer Cell, Fröhling and colleagues tackle this challenge admirably for the known cancer gene FLT3 in acute myeloid leukemia--undertaking a systematic resequencing and functional validation approach, identifying important rare driver mutations as well as passenger mutations in patients negative for the more common activating mutations.