Global gene expression changes as assessed using whole genome microarrays can provide insights into the mechanism of action of drug candidates. Signatures of gene expression can also distinguish compounds with potential to cause tissue injury with diverse mechanisms from non-toxic compounds. In the case of the liver, primary human hepatocytes are widely considered to be the most suitable to assess drug-induced gene expression changes In vitro since they contain the full repertoire of regulatory pathways. However, hepatocytes display a precipitous decline in phenotypic functions when cultured in a sandwich of extracellular matrix proteins making them generally unsuitable for chronic exposures that mimic clinically relevant dosing regimens. HepatoPac™ is used to discern the effects of acute (24 hours) and chronic (7 to 14 days) drug exposure on the transcriptome of primary human hepatocytes using the hepatotoxic and non-toxic drug pair, Troglitazone and Rosiglitazone, respectively. Dosing of human HepatoPac at reported C[max] values of Troglitazone and Rosiglitazone produced a time-dependent increase in gene expression changes over the course of 14 days.