Diarrhoeal disorders in childhood extend beyond the inflammatory bowel diseases. Persistent and severe forms of diarrhoea can occur from birth and are associated with significant morbidity and mortality. These disorders can affect not only the gastrointestinal tract but frequently have extraintestinal manifestations, immunodeficiencies and endocrinopathies. Genomic analysis has advanced our understanding of these conditions and has revealed precision-based treatment options such as potentially curative haematopoietic stem cell transplant. Although many new mutations have been discovered, there is frequently no clear genotype–phenotype correlation. The functional effects of gene mutations can be studied in model systems such as patient-derived organoids. This allows us to further characterise these disorders and advance our understanding of the pathophysiology of the intestinal mucosa. In this review, we will provide an up to date overview of genes involved in diarrhoeal disorders of early onset, particularly focussing on the more recently described gene defects associated with protein loosing enteropathy.