<p>Antibiotic stewardship programmes aim to optimise antimicrobial use to prevent the emergence of resistance species and protect patients from the side effects of unnecessary medication. The high incidence of systemic infection and associated mortality from these infections leads neonatal providers to frequently initiate antibiotic therapy and make empiric antibiotic courses one of the main contributors of antibiotic use in the neonatal units. Yet, premature infants are also at risk for acute life-threatening complications associated with antibiotic use such as necrotising enterocolitis and for long-term morbidities such as asthma. In this review, we discuss specific aspects of antibiotic use in the very low birthweight preterm infants, with a focus on empiric use, that provide opportunities for stewardship practice. We discuss strategies to risk-stratify antibiotic initiation for the risk of early-onset sepsis, optimise empiric therapy duration and antibiotic choice in late-onset sepsis, and standardise decisions for stopping empiric therapy. Lastly, review the evolving role of biomarkers in antibiotic stewardship.</p>