<p>Fluid responsiveness is the cornerstone of circulatory management in critical illness, offering a physiologically intuitive framework for guiding fluid therapy. Nonetheless, clinical experience and accumulating evidence suggest that an increase in cardiac output does not necessarily translate into improved microcirculatory perfusion, particularly during the advanced stages of critical illness. Such dissociation between macrocirculatory stabilization and persistent tissue-level hypoperfusion challenges conventional volume-centered resuscitation paradigms. This review revisits the concept of fluid responsiveness from a microcirculatory perspective and proposes endothelial integrity, rather than circulatory responsiveness alone, as an important determinant of the effectiveness of fluid therapy. By integrating classical physiology with contemporary insights into endothelial biology, this review highlights the endothelial glycocalyx as a functional interface that may influence intravascular fluid retention, vascular permeability, and hemodynamic coherence. Glycocalyx disruption, which is increasingly conceptualized as a component of “endotheliopathy” in critical illness, may be one mechanistic contributor to fluid unresponsiveness, progressive interstitial edema, and diminishing benefits of continued fluid loading. Additionally, this review discusses the implications of this framework for interpreting fluid trials, bedside assessment of tissue perfusion, and endothelial biomarker use to contextualize resuscitation strategies. Building on the established concepts of hemodynamic coherence and the revised Starling-glycocalyx model, this review introduces “fluid effectiveness” as a complementary framework alongside fluid responsiveness, providing a physiologically coherent approach to understanding when fluid therapy can translate into organ-level benefit and why this translation may fail as endothelial and glycocalyx injury progress.</p>