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Chemoresistance is a major barrier to successful chemotherapy in canine lymphomas and mammary tumors. Several mechanisms have been shown to contribute to chemoresistance in a variety of cancers. One such mechanism is the overexpression of drug efflux pumps, called multidrug transporters, that result in reduced efficacy of chemotherapy drugs and thereby lead to chemoresistance. Nuclear receptors play a major role in regulating the gene expression of these multidrug transporters. However, the expression profile of multidrug transporters and nuclear receptors is largely unknown in canine lymphoma and mammary tumor cells. The goal of this study was to determine gene expression of multidrug transporters and nuclear receptors in canine lymphoma and mammary tumor cells. We examined the expression of the pregnane xenobiotic receptor, constitutive androstane receptor, aryl hydrocarbon receptor, peroxisome proliferator-activated receptor, multidrug resistance protein 1, and multidrug resistance-associated proteins using RT-PCR with gene-specific primers on total RNA isolated from canine lymphoma and mammary tumor cells. RT-PCR results show that the nuclear receptors and multidrug transporters are differentially expressed in the canine cancer cells and may in part explain a mechanism for differential chemoresistance in canine cancer patients. This is the first study to broadly investigate gene expression of multidrug transporters and their corresponding nuclear receptors, which are transcription factors, in canine lymphoma and mammary tumor cells. Introduction Chemotherapy is commonly employed for treating canine lymphoma and mammary tumors. However, routinely used chemotherapy drugs lose their therapeutic efficacy during the later stages of treatment due to development of chemoresistance, resulting in relapse and poor clinical outcome. Multiple mechanisms may contribute to chemoresistance. In a variety of cancers, chemoresistance is associated with overexpression of multidrug transporters, such as multidrug resistance protein 1 (MDR1) and multidrug resistance-associated proteins (MRPs) (Pondugula & Mani, 2013; Borst, Evers, Kool, & Wijnholds, 2000; Marzac et al., 2011; Chen, 2010). Functionally, these transporters prevent the retention of cytotoxic drugs within tumor cells resulting in little or no cytotoxic effect. For example, MDR1, MRP1, MRP2 and MRP3 can preclude the cytotoxic effect of classical chemotherapeutics, vincristine and doxorubicin, by exporting them from tumor cells (Borst et al., 2000; Sharom, 2008, Sodani, Patel; Kathawala, & Chen, 2012; Okamura, Sakaeda, & Okumura, 2004). Chemoresistance in canine lymphoma has been shown to be associated with upregulation (i.e., an increase in expression and/or function) of MDR1 (Fan, 2008; Lee, Hughes, Fine, & Page, 1996; Moore, Leveille, Reimann, Shu, & Arias, 1995; Steingold et al., 1998). Expression of MDR1 in malignant lymphocytes at relapse was significantly higher than that found before the initiation of chemotherapy (Fan, 2008; Lee et al., 1996; Moore et al., 1995; Steingold et al., 1998; Uozurmi, Nakaichi, Yamamoto, Une, & Taura 2005). Similarly, Gene Expression of Nuclear Receptors and Multidrug Transporters in Canine Lymphoma and Mammary Tumor Cells