Retinoic acid receptors (RARs) α, β, and γ contain retinoic acid response elements (RAREs) in their promoter regions and respond to their own activation, thus forming an autoregulatory loop. We generated transgenic mice that expressed an antisense construct of the RARα. Homozygous transgenic mice demonstrated 30% to 80% reduction in RARα protein expression in various tissues. Unlike RARα null mice generated by knockout, our antisense mice demonstrated significant compensatory increases in the expression of RARβ and RARγ proteins. Coarse fur, male sterility, and low body weight were other abnormalities observed in these mice. Most importantly, lymphoma developed in 44% of our homozygous transgenic mice at an early stage of life. These data suggest that RARα is necessary for appropriate response of the RARβ and RARγ genes to physiologic changes and deregulation of the RARα in transgenic mice, which resulted in upregulation of RARβ and RARγ, can be associated with lymphomagenesis. Thus, the data support the hypothesis that a balance among the RARs is necessary for appropriate response to various homeostatic needs.