Once daily injection of existing intermediate/long-acting insulin preparations does not provide a 24-h basal insulinemia in most patients. High variability, pronounced insulin peaks, and (as a result) a high risk of nocturnal hypoglycemia only poorly simulate normal physiology. One principle to prolong insulin action is the shift of the isoelectric point of insulin towards neutral. One example is HOE 901, which shows in healthy volunteers a constant peakless profile over the entire 24-h clamp period. In 4-week trials in comparison to NPH insulin, significant lower fasting plasma glucose levels were achieved with lower rates of nocturnal hypoglycemia. Another principle to prolong insulin action is the use of soluble fatty acid acylated insulins that are bound to albumin after absorption. The combination of long- and short-acting insulins might provide the tools towards the final goal of achieving sustained normoglycemia in diabetic patients.