Glycaemic control is a key component of the successful management of Type 1 and Type 2 diabetes mellitus. Hypoglycaemia is the limiting factor in the management of diabetes because current glucose-lowering regimens are imperfect, defences against decreasing glucose levels in Type 1 and probably Type 2 diabetes are compromised, and low glucose levels have a devastating effect on the brain. Usually, hypoglycaemia precludes the maintenance of normal glucose levels. However, attempts to circumvent the barrier of hypoglycaemia safely are worthwhile because shifting glucose levels towards the nondiabetic range reduces the long-term complications of diabetes. Patient education and empowerment, appropriate self-monitoring of blood glucose, flexible drug regimens, individualized and prudent glycaemic goals, and ongoing professional support are fundamental. Iatrogenic hypoglycaemia is the result of the interplay between excess insulin and compromised glucose counter-regulation in Type 1 and probably Type 2 diabetes. Conventional and newly recognized risk factors must be addressed. Relative or absolute excess insulin occurs when: insulin (or insulin secretagogue) doses are excessive, ill-timed or of the wrong type; the influx of exogenous glucose, endogenous glucose production or insulin clearance are decreased; and insulin-independent glucose utilization or insulin sensitivity are increased. The drug regimen, food ingestion, exercise and alcohol use are under the direct control of the patient and the healthcare provider, and regimen adjustments can be used to address insulin sensitivity and clearance. Unfortunately, these conventional risk factors explain only a minority of episodes of severe hypoglycaemia and therefore the issue of compromised glucose counter-regulation must also be addressed. It is imperative to investigate the patient history for hypoglycaemia unawareness because short-term (e.g. 2 weeks) scrupulous avoidance of hypoglycaemia can restore awareness and improve defective glucose counter-regulation. Until methods of perfect insulin replacement or release are developed, improved regimens and pharmacological methods to minimize hypoglycaemia particularly during the night can be used safely to improve overall glycaemic control.