Numerous meta-analyses on inotropes (dobutamine) and inodilators (milrinone, levosimendan) suggest that their impact on survival are at best neutral (but may be deleterious) whereas levosimendan seems to have beneficial effects on survival in patients with acute heart failure (AHF) syndromes. The aim of this essay is to attempt to explain these results through a conceptual framework of cardiocirculatory (patho)physiology. Many clinical studies in AHF have been based and interpreted on a ‘cardiocentric’ framework. The three above-mentioned categories of drugs are thought to increase cardiac output (CO) by increasing only heart muscle contraction (inotropes) or by also decreasing systemic vascular resistance (inodilators). We complement this ‘cardiocentric’ framework with a more integrated one based on (i) the effects of drugs on venous return (VR), equal to CO (VR is the difference between mean systemic and right atrial pressures divided by venous resistance; maintenance of adequate VR depends on the stressed blood volume); inodilators may decrease the stressed volume and therefore may decrease VR; (ii) the coupling of the left ventricle–aorta and right ventricle–pulmonary artery (dependent on the compliance of the large arteries), which is increased by inodilators in the absence of measurable effects on arterial systemic/pulmonary pressures) and (iii) the vascular waterfall phenomenon, which explains that inodilators, by decreasing intra-organ arterial resistance, can improve organ perfusion even in previously mildly hypotensive patients (in the absence of cardiogenic shock). The challenge is to transform these concepts into clinical tools to guide therapy in AHF syndromes.