Gold nanoparticles are extensively investigated for their potential biomedical applications. Therefore, it is pertinent to thoroughly evaluate their biological effects at different levels and their underlying molecular mechanism. Frequently, there are discrepancies about the biological effects of various gold nanoparticles among the reports dealing with different models. Most of the studies focused on the different biological effects of various nano-properties of the nanomaterials. We hypothesize that the biological models with different metabolic processes would be taken into account to explain the observed discrepancies of biological effects of nanomaterials. Herein, by using mouse embryo fibroblast cell line (MEF-1) and human embryonal lung fibroblast cell line (MRC-5) as in vitro models, we studied the cellular effects of gold nanorods (AuNRs) coated with poly (diallyldimethyl ammonium chloride) (PDDAC), polyethylene glycol and polystyrene sulfonae (PSS). We found that all three AuNRs had no effects on cellular viability at the concentration of 1 nM; however, AuNRs that coated with PDDAC and PSS induced significant up-regulation of heme oxygenase-1 (HO-1) which was believed to be involved in cellular defense activities in MEF-1 but not in MRC-5 cells. Further study showed that the low fundamental expression of transcription factor Bach-1, the major regulator of HO-1 expression, in MEF-1 was responsible for the up-regulation of HO-1 induced by the AuNRs. Our results indicate that although AuNRs we used are non-cytotoxic, they cell-specifically induce change of gene expression, such as HO-1. Our current study provides a good example to explain the molecular mechanisms of differential biological effects of nanomaterials in different cellular models. This finding raises a concern on evaluation of cellular effects of nanoparticles where the cell models should be critically considered.