Salmonella enterica are Gram-negative enteric pathogens that cause typhoid fever and gastroenteritis in humans. Many bacteria, including Salmonella, use signal transduction cascades such as two-component regulatory systems to detect and respond to stimuli in the local microenvironment. During infection, environmental sensing allows bacteria to regulate gene expression to evade host immune defenses and thrive in vivo. Activation of the Salmonella two-component regulatory systems PhoP-PhoQ and PmrA-PmrB and the RcsC-RcsD-RcsB phosphorylay by specific environmental signals in the intestine and within host cells leads to several lipopolysaccharide modifications that promote bacterial survival, cationic antimicrobial peptide resistance and virulence. Many pathogens encode orthologs to Salmonella two-component regulatory systems and also modify the lipopolysaccharide to escape killing by the host immune response. However, these organisms often regulate their virulence genes, including those responsible for lipopolysaccharide modification, in ways that differ from Salmonella. Further examination of bacterial virulence gene regulation and lipopolysaccharide modifications may lead to improved antimicrobial therapies and vaccines.