The article discusses the controversies surrounding the pathophysiology of vasogenic edema in posterior reversible encephalopathy syndrome (PRES). Two main theories have been proposed: 1) severe hypertension leading to failed autoregulation and subsequent hypoperfusion, and 2) vasoconstriction and hypoperfusion causing brain ischemia and vasogenic edema. The strengths and weaknesses of these hypotheses are reviewed, including supporting evidence and clinical data from conditions associated with PRES. While the hypertension/hyperperfusion theory is more popular, the conditions associated with PRES often present with similar immune challenges and T-cell/endothelial cell activation, suggesting that systemic features and imaging findings support the older theory of vasoconstriction and hypoperfusion as the primary mechanism. The article highlights the importance of understanding the underlying biology and systemic toxicity in PRES, which may include immune system activation, endothelial cell activation and injury, and inflammatory cytokine production, leading to hypoperfusion and vasogenic edema.The article discusses the controversies surrounding the pathophysiology of vasogenic edema in posterior reversible encephalopathy syndrome (PRES). Two main theories have been proposed: 1) severe hypertension leading to failed autoregulation and subsequent hypoperfusion, and 2) vasoconstriction and hypoperfusion causing brain ischemia and vasogenic edema. The strengths and weaknesses of these hypotheses are reviewed, including supporting evidence and clinical data from conditions associated with PRES. While the hypertension/hyperperfusion theory is more popular, the conditions associated with PRES often present with similar immune challenges and T-cell/endothelial cell activation, suggesting that systemic features and imaging findings support the older theory of vasoconstriction and hypoperfusion as the primary mechanism. The article highlights the importance of understanding the underlying biology and systemic toxicity in PRES, which may include immune system activation, endothelial cell activation and injury, and inflammatory cytokine production, leading to hypoperfusion and vasogenic edema.