ΔFosB protein accumulates in the striatum in response to chronic administration of drugs of abuse, L-DOPA, or stress, triggering long lasting neural and behavioral changes that underlie aspects of drug addiction, abnormal involuntary movements (dyskinesia), and depression. ΔFosB binds AP-1 DNA consensus sequences found in promoters of many genes and can both repress or activate gene transcription. In the striatum, ΔFosB is thought to dimerize with JunD to form a functional transcription factor, though strikingly JunD does not accumulate in parallel. One explanation is that ΔFosB can recruit different partners, including itself, depending on the neuron type in which it is induced and the chronic stimulus, generating protein complexes with different effects on gene transcription. To develop chemical probes to study ΔFosB, a high-throughput screen was carried out to identify small molecules that modulate ΔFosB function. Two compounds with low micromolar activity, termed C2 and C6, disrupt the binding of ΔFosB to DNA via different mechanisms, and in in vitro assays stimulate ΔFosB-mediated transcription. In cocaine-treated mice, C2 significantly elevates mRNA levels of the AMPA glutamate receptor GluR2 subunit with specificity, a known target gene of ΔFosB that plays a role in drug addiction and endogenous resilience mechanisms. C2 and C6 show different activities against ΔFosB homodimers compared to ΔFosB/JunD heterodimers, suggesting that these compounds can be used as probes to study the contribution of different ΔFosB-containing complexes on the regulation of gene transcription in biological systems and to assess the utility of ΔFosB as a therapeutic target.