Retinoid X receptor (RXR) is a combinatorial partner for one third of the 48 human nuclear receptor superfamily members and acts as a master coordinator of nuclear receptor signaling pathways involved in the control of cell growth and differentiation. Thus, ligand-dependent simultaneous activation of multiple pathways is an attractive strategy for molecular-targeted therapy of neoplastic disease. However, clinical trials in RXR-targeted molecular therapy with the RXR ligand (rexinoid) have yielded disappointing outcomes. In this review, we discuss a possible mechanism underlying the loss of sensitivity to rexinoid therapy.