Mutations in transthyretin (TTR) are the most common cause of autosomal dominant systemic amyloidosis. To date, more than 80 TTR mutations have been associated with amyloidosis in humans. A high prevalence of some mutations like Val122Ile which is identified in 3% of African Americans indicates the necessity of thorough investigation of patients suspected of having, or to be at risk of developing, TTR amyloidosis. Laboratory tests available for evaluation of TTR amyloidosis include both DNA and protein assays. In the case of a known mutation DNA analysis is realized by restriction fragment length polymorphism (RFLP), polymerase chain reaction-induced mutation restriction analysis (PCR-IMRA), single strand confirmation polymorpism (SSCP) or nucleotide sequencing. SSCP, PCR-non-isotopic RNAse cleavage assay (NIRCA) or nucleotide sequencing are used to identify an unknown mutation. At the protein level, two techniques are used, isoelectric focusing and mass spectrometry, in both cases (known or unknown mutation). The identification of a previously unknown mutation requires a combination of clinical, pathological and molecular studies.