Systemic antibiotics are the group of drugs most commonly used in children. Off-label antibiotic use in children is still common in the community and in hospitals, mostly because of young age, dosage, or frequency of drug application. There is an important incentive gap that hinders paediatric drug development resulting from a series of factors, such as small market size, a predominance of off-patent use, no incentives for generic drug manufacturers, and a greater complexity of drug development. The latter is due to varying capacities of drug absorption and metabolism during growth and maturation and the need for oral formulations in neonates and infants. High ethical barriers, combined with concerns of parents about drug safety, further complicate the conduct of clinical studies in children. While many off-patent antibiotics today are labelled for use in children, newer substances such as fluoroquinolones, azithromycin, linezolid, or daptomycin are not. This is of concern in the light of emerging multidrug-resistant pathogens.