Thiamine or vitamin B1 is a water-soluble vitamin. It is synthetized by bacteria, fungi, and plants, yet humans are unable to synthesize thiamine and must therefore acquire it through their diet. Thiamine has a vital role in a series of metabolic processes related to energy production, catabolism of carbohydrates, and amino acids. It is involved in the synthesis of neurotransmitters and has a main role in the central nervous system (CNS) function. Thiamine deficiency can arise from several etiological factors, including genetic inborn errors of thiamine metabolism and transport, malnutrition, malabsorption, enhanced metabolic demands, or by increased losses. The clinical presentation of thiamine deficiency varies and can range from CNS involvement as typically seen in Wernicke–Korsakoff syndrome or heart failure as in beriberi syndrome. The various genetic syndromes associated with the metabolism and transport of thiamine each have unique clinical characteristics depending on the affected protein. Thiamine deficiency should be considered in all pediatric patients with severe malnutrition or with episodes of recurrent encephalopathy or dystonia, increased blood lactate or CSF, or increased alpha-ketoglutarate in urine as well as in patients with radiological injury of basal ganglia and thalami. Suspicion is essential since early treatment has been shown to improve prognosis in most patients. In this review, we will further discuss the history of thiamine, its metabolic and physiologic role, the different clinical presentations, the genetic point of view, and treatment.