The transcription factor ΔFosB (Delta FosB) accumulates in a region-specific manner in the brain during chronic exposure to stress, drugs of abuse or other chronic stimuli. Once induced, ΔFosB persists in the brain for at least several weeks following cessation of the chronic stimulus. The biochemical basis of the persistent expression of ΔFosB has remained unknown. Here, we show that the FosB C-terminus, absent in ΔFosB as a result of alternative splicing, contains two degron domains. Pulse-chase experiments of C-terminal truncation mutants of full-length FosB indicate that removal of its most C-terminal degron increases its half-life ∼ fourfold, and prevents its proteasome-mediated degradation and ubiquitylation, properties similar to ΔFosB. In addition, removal of a second degron domain, which generates ΔFosB, further stabilizes FosB ∼ twofold, but in a proteasome-independent manner. These data indicate that alternative splicing specifically removes two destabilizing elements from FosB in order to generate a longer-lived transcription factor, ΔFosB, in response to chronic perturbations to the brain.