Intravenous fluid administration is a cornerstone of intensive care resuscitation. When considering fluid therapy, clinicians must attempt to answer two fundamental questions: (1) Is an increase in cardiac output likely to reverse or improve a hypoperfusion state? and (2) Is a fluid bolus likely to increase the cardiac output? Recent data on the potentially harmful effect of fluid overload in ICU patients have led intensivists to reconsider the sacrosanct practice of the “fluid challenge”. As such, various predictors of fluid responsiveness have been proposed as potential alternatives to inform clinicians on the best course of action. A better understanding of the largely ignored basic physiologic mechanisms that determine fluid responsiveness can inform the choice of available bedside maneuvers, interpretation of data, and use of available technologies in hypoperfused patients.