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The synthesis of peptides heavily based on C-alpha-tetrasubstituted alpha-amino acids is a rather difficult task as the reactivity of these building blocks in amide bond formation is generally poor, which primarily results from the severe steric hindrance of the amino functionality. Nevertheless, such a synthetic approach is very relevant in view of the current extensive utilization of these peptides as membrane-active, antimicrobial, compounds and conformationally restricted, tunable, spacers and templates in modern organic and physical chemistry investigations. In this Account we discuss new mechanistic information, drawbacks, improvements, and successful results published over the years by a number of research groups with special emphasis on the problems encountered and (often) solved in our own journey through this fascinating field. 1 Introduction 2 Work on Aib Peptides before 1980 2.1 Synthesis 2.2 Conformation 3 Synthetic and Structural Work on Peptides Based on Aib and Related Amino Acids since 1980 4 Structural Work on Derivatives of Aib and Related Amino Acids 5 Conclusions and Outlook.