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As in vitro assays are increasingly used to screen chemicals for their potential to produce endocrine disrupting adverse effects, it is important to understand their predictive capacity. The potential for a set of 6 benzothiazoles to affect endpoints related to thyroid hormone synthesis inhibition were assessed using in vitro, ex vivo, and in vivo assays. Inhibition of thyroid peroxidase (TPO) derived from pig thyroid glands was determined for benzothiazole (BTZ), 2-mercaptobenzothiazole (MBT), 5-chloro-2-mercaptobenzothiazole (CMBT), 2-aminobenzothiazole (ABT), 2-hydroxybenzothiazole (HBT), and 2-methylthiobenzothiazole (MTBT). Their rank order potency for TPO inhibition was MBT=CMBT>ABT>BTZ, whereas HBT and MTBT exhibited no inhibitory activity. The benzothiazoles were tested further in a Xenopus laevis thyroid gland explant culture assay in which inhibition of thyroxine (T4) release was the measured endpoint. In this assay all 6 benzothiazoles inhibited T4 release. The activity of the benzothiazoles for disrupting thyroid hormone activity was verified in vivo using X. laevis tadpoles in a 7-day assay. The 2 most potent chemicals for TPO inhibition, MBT and CMBT, produced responses in vivo indicative of T4 synthesis inhibition including induction of sodium iodide symporter mRNA and decreases in glandular and circulating thyroid hormones. The capability to measure thyroid hormone levels in the glands and blood by ultrahigh performance LC-MS/MS methods optimized for small tissue samples was critical for effects interpretation. These results indicate that inhibition of TPO activity in vitro was a good indicator of a chemical's potential for thyroid hormone disruption in vivo and may be useful for prioritizing chemicals for further investigation.