New data, published in Nature, show that forkhead box protein A1 (FOXA1) alterations in prostate cancer can be categorized into three distinct structural classes. Analysis of an aggregate cohort of 1,546 prostate cancers showed that these three classes have a collective incidence of 35% but divergent clinical incidence and genetic co-alteration profiles. Class 1 activating mutations occur early in disease, acquisition of class 2 activating mutations occurs in metastatic disease and class 3 genomic rearrangements are enriched in metastatic prostate cancer. Improved understanding of the mechanisms and the roles of the classes of FOXA1 in the initiation and/or progression of prostate cancer provides a rationale for therapeutic targeting of this transcription factor.