Ejection Fraction (EF) has attained the recognition as indicator of global ventricular performance. Remarkably, precise historical origins promoting the apparent importance of EF are scant. During early utilization EF has been declared a gold standard for the evaluation of the heart as a pump. In contrast, during the last two decades, clinicians have developed a measure of doubt in the universal applicability of EF. This reluctance lead to the introduction of a new and prevalent syndrome in which heart failure (HF) is diagnosed as having a preserved EF (pEF). We examine the existing criticism regarding EF, and describe a novel avenue to characterize ventricular function within the unifying framework of cardiac input-output volume regulation. This approach relates end-systolic volume (ESV) to end-diastolic volume (EDV), and derives for a subgroup matching pEF criteria a distinct pattern in the ESV-EDV domain. In patients with pEF (n = 34), a clear difference (P < 0.0004) in the slope of the regression line for ESV versus EDV was demonstrated compared to control patients with EF < 50% (n = 29). These findings are confirmed by analysis of data presented in two independent publications. The volume regulation approach proposed employs primary end-point determinants (such as ESV and EDV) rather than derived quantities (e.g., the ratio EF or its differential parameter, that is, stroke volume) and confirms a distinct advantage over the classical Starling curve. Application of the ESV-EDV-construct provides the basis and clarifies why some patients present as HFpEF, while others have reduced EF.