Fatty acids (FAs) consist of long hydrophobic, often unbranched chains of hydrocarbons, with hydrophilic carboxylic acid groups at one end. They are an important source of reserve energy and essential components of membrane lipids in all living organisms. In plants, FA metabolic pathways play significant roles in pathogen defense. Historically, FAs were only assigned passive roles in plant defense such as biosynthetic precursors for cuticular components or the phytohormone jasmonic acid. However, recent discoveries demonstrate more direct roles for FAs and their breakdown products in inducing various modes of plant defenses. Both 16- and 18-carbon FAs participate in defense to modulate basal, effector-triggered, and systemic immunity in plants. Studies of FA metabolic mutants also reveal an active signaling role for the cuticle in plant defense. This review summarizes the current knowledge of the involvement of FAs, FA-derived oxylipins, and enzymes catalyzing FA metabolism in plant defense.