Gene regulation underlies all functional outputs of a cell. Measuring changes in gene expression during biological processes is now routine; however, understanding how complex gene regulatory responses affect cellular functions remains a challenge. To address this problem, I developed network-based strategies to interrogate publicly available gene expression data to better understand how Caulobacter crescentus survives stress. My approach identified GsrN, a conserved small RNA that is directly activated by the general stress sigma factor, σT. I found that GsrN functions as a potent post-transcriptional regulator of survival across distinct conditions including osmotic and oxidative stress. To understand GsrN’s role in stress adaptation, I developed a forward biochemical approach to identify the molecular partners of GsrN. This methodology identified the leader of katG mRNA, the sole catalase/peroxidase gene in Caulobacter crescentus, as a regulatory target of GsrN. I further demonstrated that GsrN base pairs to the leader of katG mRNA and activates expression of KatG. In summary, my dissertation outlines new computational and experimental approaches that led to new understanding of the regulation of Caulobacter crescentus stress physiology.