The art of transforming peptides into drug leads is still a powerful and fertile field in medicinal chemistry and drug discovery. Peptidomimetics can respond to peptide limitations by displaying higher metabolic stability, good bioavailability and increasing receptor affinity and selectivity. Various synthetic approaches and strategies have been developed over the years in order to modulate the conformational flexibility and the peptide nature of peptide mimetic compounds. This review aims to outline useful tools towards peptide mimetic design, spanning from local modifications, global restrictions and the use of secondary structure mimetics. Key learning points: Advantages of peptidomimetics over peptides, definition and classification of peptide mimetics, synthetic strategies and molecules for local modifications, secondary structure mimetics, global restrictions and Applications of peptide mimetics in drug discovery. Selected best examples of each approach are presented to document the relevance of peptidomimetics in new drug discovery.