Peptide　therapeutics　have　gained　great　interest　due　to　their　multiple　advantages　over　small　molecule　and　antibody-based　drugs.　Peptide　drugs　are　easier　to　synthesize,　have　the　potential　for　oral　bioavailability,　and　are　large　enough　to　target　protein-protein　interactions　that　are　undruggable　by　small　molecules.　However,　two　major　limitations　have　made　it　difficult　to　develop　novel　peptide　therapeutics　not　derived　from　natural　products,　including　the　metabolic　instability　of　peptides　and　the　difficulty　of　reaching　antibody-like　potencies　and　specificities.　Compared　to　linear　and　disulfide-monocyclized　peptides,　multicyclic　peptides　can　provide　increased　conformational　rigidity,　enhanced　metabolic　stability,　and　higher　potency　in　inhibiting　protein-protein　interactions.　The　identification　of　novel　multicyclic　peptide　binders　can　be　difficult,　however,　recent　advancements　in　the　construction　of　multicyclic　phage　libraries　have　greatly　advanced　the　process　of　identifying　novel　multicyclic　peptide　binders　for　therapeutically　relevant　protein　targets.　This　review　will　describe　the　current　approaches　used　to　create　multicyclic　peptide　libraries,　highlighting　the　novel　chemistries　developed　and　the　proof-of-concept　work　done　on　validating　these　libraries　against　different　protein　targets.　©　2024　Wiley-VCH　GmbH.