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We have characterized initial canonical responses to two environmental toxicants, cadmium (Cd) and benzo[a]pyrene (B[a]P), in a novel in vitro model derived from renal proximal tubule epithelial cells (RPTEC) of a healthy human donor. The RPTEC/TERT1 cell line has been immortalized using the human telomerase reverse transcriptase (hTERT) subunit only and does not exhibit chromosomal abnormalities. RPTEC/TERT1 cells were exposed to single-compound and binary mixtures of Cd and B[a]P, known or suspected renal toxicants respectively. Cells exhibited cytotoxicity to concentrations of B[a]P and Cd as low as 1 nm and 3 μM, respectively. RPTEC/TERT1 cells exhibited compound-specific gene expression responses when exposed to 0.01–1 μM B[a]P and 0.1–10 μM Cd. A significant increase in the expression of genes coding for B[a]P metabolizing enzymes (CYP1A1, CYP1B1) occurred in a dose and time dependent manner at 3, 6, and 24 h post exposure. Likewise, a significant increase in the heavy metal responsive gene MT2A was observed following exposure to Cd. The EROD activity assay confirmed significant increases in CYP1(A/B) activity after 24 h of exposure to B[a]P which was not affected by the presence of Cd. Co-exposure to low concentrations of Cd and B[a]P were consistent with changes in gene expression as seen with single-compound exposures. These experiments are the first to provide information regarding toxicological responses in the RPTEC/TERT1 cell line that model those of the target tissue. We conclude that these cells can provide a useful tool for future toxicological studies.