Accumulating evidence has shown a link between environmental contaminants and altered lipid metabolism. There is currently, however, limited knowledge regarding the causal molecular mechanisms. Therefore, we investigated the molecular mechanisms of two environmental contaminants, ivermectin and perfluorobutanesulfonic acid (PFBS), on lipid metabolism in adipocytes and hepatocytes using cell culture models. We first studied the effects of ivermectin, an anti-parasitic agent, on the adipogenesis of 3T3-L1 preadipocytes. Our current results suggest that ivermectin inhibits adipogenesis in 3T3-L1 preadipocytes and the expression of adipogenic genes where these effects were found to be partially via PPARγ-dependent, but not FXR-dependent, pathway. Additionally, ivermectin also activates the expression of glycine receptor subunits, potentially related to the inhibitory effect on adipogenesis. PFBS is the replacement of perfluorooctanesulfonic acid, which has been reported to disrupt lipid metabolisms. There is no report, however, of the effect of PFBS on lipid metabolisms. We found that PFBS treatment extensively promoted the differentiation of 3T3-L1 preadipocytes, resulting in significantly increased TG levels. The effects of PFBS were found to target the early stage of differentiation, in particular via MEK/ERK-dependent pathway. The effects of PFBS on hepatic lipid metabolisms were also investigated by using HepG2 hepatocytes. The current results suggested that PFBS increased the hepatic TG accumulation when supplemented with fatty acid mixture. The effects were also found mediated by PPARγ-mediated pathways.