Polymer brushes have been utilized as a proper model interface for the investigation of wetting, lubrication, hydrated chain dimension and the structure of hydrated water at hydrated polymer interfaces. Zwitterionic polyelectrolyte-tethered surfaces represent significant anti-fouling materials for bio-macromolecules, marine fouling organisms and pipeline foulants. Systematic anti-fouling tests for various polymer brushes were performed to demonstrate the critical factors for universal anti-fouling properties. In this focused review, material design concepts and recent progress on anti-fouling polymer materials are reviewed, and our recent research on anti-fouling studies using polymer brushes is provided.