Chapter 1 The background of peptides as therapeutics and anti-cancer agents is discussed in this chapter. The development for peptide synthesis via both solution and solid phase is introduced as well as the macrocyclization strategies. Chapter 2 Sansalvamide A (SanA) exhibits anti-cancer potency in the micromolar range against multiple cancer cell lines. Structure-activity relationship (SAR) and the mechanistic studies of SanA have been investigated in our lab. This chapter focuses on the design and synthesis of SanA derivatives. Five SanA derivatives were designed based on the lead compounds in SanA project. The synthesis of these derivatives was accomplished via both solution and solid phase peptide synthesis. Studies for SAR and mechanism of action are also discussed in this chapter. Chapter 3 The novel macrocyclic peptide Urukthapelstatin A (Ustat A) possesses a unique scaffold featuring five directly-linked azoles. Ustat A exhibits nanomolar cytotoxicity against cancer cells yet its mechanism of action remains undefined. This chapter focuses on the synthesis of Ustat A and its derivatives. The design of Ustat A derivatives is depicted and the synthestic approaches are illustrated. In addition, several strategies for cyclizing the Ustat A macrocycle are discussed. Finally, the cytotoxicity of synthetic Ustat A and its fragments is also demonstrated.