The diagnostic material in hematopathology consists almost exclusively of tissue specimens fixed in formalin and embedded in paraffin (FFPE). Although morphologic, immunophenotypic and cytogenetic procedures are well established for use with FFPE samples, PCR-based applications suffer from the degradation of nucleic acids by formalin fixation. This holds especially true for complex multiplex PCRs such as for the detection of clonally rearranged antigen receptor (T cell and immunoglobulin) genes. Here, we describe pitfalls and limitations of clonality PCR assays based on FFPE samples and provide recommendations for proper implementation in a molecular pathology lab. Moreover, specific aspects for the reliable interpretation of the clonality PCR data derived from FFPE samples are considered. This information provides an excellent basis for this important supplementary molecular diagnostic test in hematopathology.