Short tandem repeat (STR) analysis has emerged as the method of choice for testing to resolve specimen source contamination and identity problems that arise in surgical pathology. We studied a series of consecutive cases referred for STR typing during a 5-year period to document the usefulness of the approach and to describe the broadening scope of testing. The series demonstrates that STR-based typing can be applied in virtually any setting in which specimen source confirmation is requested, that STR-based typing is informative in 92% of cases, but that exceptions occasionally arise that complicate test interpretation. The series also demonstrates that in addition to traditional uses of STR typing, testing is now performed in the absence of any direct indication that a specimen mix-up or contamination may have occurred, namely, when the pathologic findings are unexpected or the clinical setting is atypical. The case series underscores the ability of STR testing to detect errors that cannot be captured by current laboratory protocols, a finding that has important implications for patient safety.