In 2001, Rivers and colleagues published a randomized controlled trial of early goal-directed therapy (EGDT) for the treatment of sepsis. More than a decade later, it remains a landmark achievement. The study proved the benefits of early aggressive treatment of sepsis. However, many questions remain about specific aspects of the complex EGDT algorithm. Recently, 3 large trials attempted to replicate these results. None of the studies demonstrated a benefit of an EGDT protocol for sepsis. This review explores the physiologic basis of goal-directed therapy, including the hemodynamic targets and the therapeutic interventions. An understanding of the physiologic basis of EGDT helps reconcile the results of the clinical trials.