Nearly all humans are exposed to stress. However, most individuals do not develop depression. This is modeled in animal stress paradigms such as chronic social defeat stress (CSDS) in which only a subset of exposed mice display depression-like behavior. RNA-seq studies in these animals report broad transcriptional adaptations in stress resilience. How these transcriptional changes are regulated, however, is not known. In this thesis, I utilize a combined bioinformatics and in vivo molecular approach to probe the mechanisms underlying transcriptional changes in resilience. I first performed upstream regulator analysis on differentially expressed genes following CSDS and identified estrogen receptor alpha (ERalpha) as the top upstream regulator of pro-resilient transcription in the nucleus accumbens (NAc), a brain region implicated in depression. Overexpression of ERalpha in the NAc promoted resilience to stress in both male and female mice. However, while ERalpha overexpression recapitulated the transcriptional signature of resilience in male mice, this was not the case for female mice, indicating a sex-specific transcriptional mechanism. I next evaluated a WGCNA dataset of resilient mice following CSDS, identifying a resilient-specific transcriptional network. Using key driver analysis, I found that Zfp189 was the top regulator and was upregulated in the prefrontal cortex (PFC) of resilient mice, another brain region implicated in depression. Overexpression of Zfp189 in the PFC was both pro-resilient and antidepressant, and significantly upregulated genes in the resilient-specific network where Zfp189 was the top regulator. Further interrogation of known binding motifs within this network identified CREB as a predicted upstream regulator and re-analysis of previously published ChIP- chip data defined a known molecular interaction between CREB and Zfp189. Consistent with these observations, knockout of CREB in the PFC increased susceptibility to stress, but the deleterious effects of CREB knockout were ablated by Zfp189 overexpression. In order to probe this connection directly, I utilized CRISPR to mimic endogenous CREB-Zfp189 interactions in vivo in the PFC. This was both sufficient to increase behavioral resilience and activate the resilient-specific network. As a whole, these findings provide novel mechanistic insight into the regulation of transcriptional changes in stress resilience.