Attempts to produce animal models of the human transthyretin deposition disorders have not been as successful as investigators would wish. While random genomic insertion of mutant and wild-type human transthyretin genes has, in some instances, produced tissue deposits consisting of the human protein, in no case has a model faithfully reproduced the neuropathic pathology seen in FAP patients. Examining all the available models it appears that overexpression of the human construct is required with a resultant high level of protein production, as measured by the serum concentration. Animals, homo- or heterozygous for a single copy of a naturally occurring mutant human gene, even a thermodynamically unstable allele (leu55pro), do not develop immunohistochemically detectable tissue deposits. If the endogenous murine gene is subjected to targeted disruption, a small proportion of animals will develop tissue deposits of the human protein late in life. The implication of this observation is that the murine protein may stabilize mixed tetramers containing both mutant human and wild-type murine monomers in a manner similar to that seen in humans with the Met119 variant. As in humans with FAP or FAC, parenchymal hepatic deposition of either fibrillar or non-fibrillar deposits is uncommon. When TTR concentrations are similar in liver and kidney extracts, kidneys show evidence of aggregate deposition while livers do not. At least one of the transgenic models shows that non-fibrillar deposits precede the appearance of Congophilic tissue deposition, a circumstance that has also been seen in early neuropathic lesions of FAP patients. While none of the current models is a precise replicant of the human disease, the tissue specificity of deposition, the relationship to age in some models, the apparent sequential nature of the form of the deposits, and the sensitivity to the presence or absence of other gene products all reflect properties shared with FAP, FAC and SSA. They thus represent experimental systems for exploring factors and generally approachable in intact humans and reasonable screening tools for the effectiveness of various therapeutic approaches.