Environmental contaminants are known to act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are xenobiotics that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeostasis or change circulating or tissue concentrations of THs. For THs, homeostasis is defined as the normal range of THs and TSH in circulation and tissues. TDCs include a wide range chemical structures that act through a variety of mechanisms. Concern about TDCs has increased because of the critical role that thyroid hormones play in brain development. A major uncertainty regarding the endocrine disrupting potential of environmental xenobiotics is the potential for additive, antagonistic or synergistic effects following exposure to mixtures. In addition, there are a number of uncertainties in both interpretation and extrapolation of results from studies of TDC mixtures. Extrapolation of data from laboratory animals to humans is tempered by uncertainty in how the mechanism(s)-of-action of the TDCs may differ between species. The variety of mechanisms by which TDCs alter thyroid homeostasis also yields a difficulty in determining at what level of biological organization to cumulate effects. Should it be at the molecular level, which could be chemical class specific or at the level of a downstream consequence (e.g. circulating hormone levels, brain biochemistry and behaviour) which would be mechanism-independent? To date, the limited data from TDC mixture studies suggest that dose addition is reasonably accurate in predicting the effects on serum T4 concentrations. Assessing the health risks of thyroid disruption by environmental xenobiotics will need to include an improved understanding of how divergent mechanisms alter THs and consequent adverse impacts on nervous system development.