Transthyretin is an amyloidogenic protein associated with several amyloidosis, namely familial amyloidotic polyneuropathy, familial amyloidotic cardiomyopathy, and central nervous system selective amyloidosis, familial rare diseases caused by single point mutants, and senile systemic amyloidosis associated with wild-type TTR. The current model for amyloid fibril formation involves initial dissociation of the native TTR tetramer into non-native monomers which associate into soluble oligomers and protofibrils that evolve to mature amyloid deposits. A number of efforts are addressed to identify small molecules targeting the formation, clearance, or assembly of toxic aggregates as a promising therapeutic strategy to treat amyloidosis. This review classifies and summarizes the different strategies and assays that have been developed in vitro, ex vivo, and in vivo as tools to screen libraries of compounds or to test compounds from rational design in the search of drug candidates for the treatment of TTR-associated amyloidosis. Depending on the property they measure, the assays are classified as: a) in vitro assays that monitor protein aggregation and/or fibril formation, b) in vitro assays that monitor binding to native protein, c) ex vivo TTR plasma selectivity assays, d) in vitro assays for tetrameric TTR stabilization, e) cellular assays, and f) animal models to evaluate amyloidosis inhibitors.