P53 is the most commonly altered tumor-suppressor gene in humans, involved in the development and progression of many diverse forms of human cancer. Although much remains to be learned about the biology of this important growth regulatory gene, sufficient experience has been accumulated with respect to the occurrence and pattern of p53 mutational change to justify molecular diagnostic testing for specific objectives. The authors outline specific concepts for testing with particular emphasis for solid tumor molecular diagnostics. This article focuses on microdissection-based fixed tissue molecular analysis, introducing new considerations related to quality control appropriate for this type of methodology. Given the rapidly evolving nature of molecular genetics, the suggestions provided here should be viewed as flexible. Nevertheless, the concepts are intended to serve as a model for other oncogene/tumor suppressor-gene assays to be developed with the overall purpose of establishing informative integrated histopathologic/genetic molecular diagnostic testing to complement standard microscopic analysis.