Devices that continuously measure relative blood volume (RBV) changes during hemodialysis (HD) are increasingly used for the prevention of dialysis hypotension and fine-tuning of dry weight. However, RBV measurements are subject to various limitations. First, RBV devices provide information on relative blood volume changes but not on absolute blood volume. Since blood volume varies with the hydration status, identical reductions of RBV may result in very different absolute blood volumes at the end of HD. Second, RBV changes underestimate the change of total blood volume due to translocation of lower-hematocrit blood from the microcirculation to the central circulation. Third, changes in posture before and during HD, food intake, exercise, and administration of intravenous fluids may influence the validity of the RBV measurement. Fourth, results obtained by various RBV devices show large interdevice differences. Finally, although a fall in blood volume is an important factor in dialysis hypotension, frank dialysis hypotension only occurs when the cardiovascular compensatory mechanisms can no longer compensate for the reduction in blood volume. Therefore, the dialysis staff should not exclusively focus on RBV, but also search for opportunities in the dialysis prescription to facilitate cardiovascular compensatory mechanisms, e.g. by lowering dialysate temperature. In the opinion of the authors, routine RBV monitoring should be used with caution until the major conceptual and methodological problems that are inherent to the indirect RBV estimation are clarified.