Small RNAs are named for their small (20–24 nucleotide) size, but the impact of their function on nearly all organisms, including animals, plants, and fungi, is profound. Many studies have shown that these non-coding RNAs regulate gene expression by silencing genes during plant pathogen infection and determine the outcome—host survival or eventual death. In this dissertation, I present my studies investigating the role of small RNAs in the interactions between the plant Arabidopsis thaliana and the hemibiotrophic bacterial pathogen Pseudomonas syringae. Chapter 1 is an introduction to this dissertation and broadly covers relevant topics such as the plant immune system, small RNA biogenesis, the role of small RNAs in plant bacterial resistance, RNA-directed DNA methylation, and the role of DNA methylation in plant bacterial resistance. Chapter 2 is a reprint of our publication titled “miRNA863-3p sequentially targets negative immune regulator ARLPKs and positive regulator SERRATE upon bacterial infection”. We discovered that miRNA863-3p is highly induced by Pseuduomonas syringae pv. tomato containing effector gene avrRpt2, and it sequentially targets ARLPKs, which are receptor-like psuedokinases that have negative roles in plant defense, and SERRATE, which has a positive role in defense and a known role in miRNA biogenesis. Chapter 3 is a report on our finding that the pol IV mutant exhibits enhanced resistance to bacterial infection, but cannot be primed for systemic acquired resistance (SAR) with Psuedomonas syrginae pv. maculicoli (Psm), and whole genome bisulfite sequencing and further analysis revealed that SCR-LIKE 5 (SCRL5) has increased DNA methylation and decreased relative expression after wild-type plants are pre-treated with Psm, but this change in methylation and gene expression is not seen in pol IV. Furthermore, SCRL5 is upregulated in local infections with P. syringae pv. tomato, suggesting that it may have a complex role in local and systemic defense. Lastly, Chapter 4 is a report of a forward chemical genetics screen conducted using “Library of AcTive Compounds on Arabidopsis to find small molecules that perturb a nat-siRNA pathway. We identified 11 small molecules possibly targeting this pathway that can be used for further testing.