MicroRNAs (miRNAs) derived from the cell-free fractions of blood are emerging as useful noninvasive markers of cancer. However, many tumors display significant molecular heterogeneity, which is likely to be reflected in the circulating miRNA fingerprints associated with that pathology. One strategy to minimize such heterogeneity is to employ genetically engineered mouse models of human cancer. Here, we describe a method to profile miRNAs in the serum of a mouse model of prostate cancer, TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP), and discuss practical considerations for translating these potential biomarkers into a clinical setting.