The indications and contraindications of parenteral nutrition (PN) are discussed in view of recent clinical findings. For decades, PN has been restricted to patients unable to tolerate enteral nutrition (EN) intake owing to the perceived risk of severe side-effects. The evolution of the PN substrate composition and delivery of nutrition via all-in-one bags has dramatically improved the application prospects of PN. Recent studies show similar complication rates of nutrition therapy administered through enteral and intravenous routes. Therefore, indications of PN have, based on evidence, extended beyond complete gastrointestinal (GI) failure to include conditions such as insufficient EN generating persistent negative energy balance and insufficient protein intakes, malabsorption, or specific needs that are impossible to cover with EN feeds.