Some general features of dexamethasone resistance in five murine lymphoid cell lines were investigated. To obtain large numbers of dexamethasone-resistant (Dexr) variants, a technique was developed by which mouse lymphoid cell lines can be grown with high efficiency on the surface of agar plates without a feeder layer. A total of 271 Dexr variants were investigated, and 90% of them turned out to lack detectable steroid receptor whereas 10% have receptor with, in most cases, a normal affinity for the steroid hormone. Most of this latter class of variants, however, have reduced amounts of receptor and the receptor of all of them displayed altered nuclear binding characteristics. None of the five investigated lymphoid cell lines yielded a Dexr variant with a normal receptor. These results confirm the idea that the high incidence of receptor variant may be due, at least in part, to the haploid state of a gene coding for the receptors. In cell fusion experiments it could be shown that Dexs is dominant over Dexr, but that a Dexr a-lele in a tetraploid cell can lead to an increased frequency of steroid resistance.