Molecular testing in pathology emerged shortly after polymerase chain reaction became a standard molecular biology assay. Testing efforts began in the clinical laboratories primarily with assays for genetically inherited diseases and assays for clonality in hematologic malignancies. Today, the field has evolved into "molecular diagnostics," which encompasses testing in almost every area of anatomic pathology. Molecular testing is now even making its way definitively into both surgical pathology and cytopathology, although molecular anatomic pathology is still young with few standard tissue-based molecular assays. As more clinically valuable information is gained from molecular pathology testing of tissues, unique challenges are also becoming apparent at the intersection between tissue diagnosis and DNA diagnosis. This review focuses on basic molecular pathology concepts, with particular emphasis on the challenge of tissue-based testing in anatomic pathology.