BACKGROUND Although serum osmolal gap can be a useful diagnostic tool, clinicians are not familiar with its use in clinical practice. OBJECTIVE The review presents in a series of questions-answers and under a clinical point of view the current data regarding the use of osmolal gap. CONCLUSIONS The definition and the best formula used for the calculation of osmolal gap, the main causes of increased osmolal gap with or without increased anion gap metabolic acidosis, as well as the role of concurrent lactic acidosis or ketoacidosis are presented under a clinical point of view. CONCLUSIONS The calculation of osmolal gap is crucial in the differential diagnosis of many patients presenting in emergency departments with possible drug or substance overdose as well as in comatose hospitalized patients.