Systemic acquired resistance (SAR) is a mechanism of induced defense that confers long-lasting protection against a broad spectrum of microorganisms. SAR requires the signal molecule salicylic acid (SA) and is associated with accumulation of pathogenesis-related proteins, which are thought to contribute to resistance. Much progress has been made recently in elucidating the mechanism of SAR. Using the model plant Arabidopsis, it was discovered that the isochorismate pathway is the major source of SA during SAR. In response to SA, the positive regulator protein NPR1 moves to the nucleus where it interacts with TGA transcription factors to induce defense gene expression, thus activating SAR. Exciting new data suggest that the mobile signal for SAR might be a lipid molecule. We discuss the molecular and genetic data that have contributed to our understanding of SAR and present a model describing the sequence of events leading from initial infection to the induction of defense genes.