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Gene repression by transcription factors, and glucocorticoid receptors (GR) in particular, is a critical, but poorly understood, physiological response. Among the many unresolved questions is the difference between GR regulated induction and repression, and whether transcription cofactor action is the same in both. Because activity classifications based on changes in gene product level are mechanistically uninformative, we present a theory for gene repression in which the mechanisms of factor action are defined kinetically and are consistent for both gene repression and induction. The theory is generally applicable and amenable to predictions if the dose-response curve for gene repression is non-cooperative with a unit Hill coefficient, which is observed for GR-regulated repression of AP1LUC reporter induction by phorbol myristate acetate. The theory predicts the mechanism of GR and cofactors, and where they act with respect to each other, based on how each cofactor alters the plots of various kinetic parameters vs. cofactor. We show that the kinetically-defined mechanism of action of each of four factors (reporter gene, p160 coactivator TIF2, and two pharmaceuticals [NU6027 and phenanthroline]) is the same in GR-regulated repression and induction. What differs is the position of GR action. This insight should simplify clinical efforts to differentially modulate factor actions in gene induction vs. gene repression., Author Summary While the initial steps in steroid-regulated gene induction and repression are known to be identical, the same cannot be said of cofactors that modulate steroid-regulated gene activity. We describe the conditions under which a theoretical model for gene repression reveals the kinetically-defined mechanism and relative position of cofactor action. This theory has been validated by experimental results with glucocorticoid receptors. The mode and position of action of four factors is qualitatively identical in gene repression to that previously found in gene induction. What changes is the position of GR action. Therefore, we predict that the same kinetically-defined mechanism usually will be utilized by cofactors in both induction and repression pathways. This insight and simplification should facilitate clinical efforts to maximize desired outcomes in gene induction or repression.