Solid phase peptide synthesis (SPPS), first proposed by R. B. Merrifield in 1962, has evolved over three decades into a tremendously powerful method for the preparation of peptides and small proteins. An absolute prerequisite for successful syntheses in all solid phase schemes is that reactions which accumulate solid supported products, and by the very nature of the technique contaminating by-products, must proceed cleanly and efficiently. During the earlier years of SPPS this optimal situation was not always achieved, primarily due to contaminated reagents and ill-defined polymers in combination with poorly flexible protection strategies. As the methods of SPPS gained popularity and more widespread application, reagents and protection strategies were improved and refined. However, reports of notable successful syntheses were accompanied by then unexplained failures, which have since been collectively termed ‘difficult peptides’. This chapter describes how an intrinsic understanding behind the occurrence of ‘difficult peptides’ has accumulated, leading to a general synthetic solution—the utilization of a backbone amide protection strategy. Within a few years of the introduction of SPPS, it was recognized that the assembly of some peptide sequences posed a special synthetic problem. The main feature evident during these syntheses was a sudden decrease in reaction kinetics, leading to incomplete amino-acylation by activated amino acid residues. The unreacted sites were readily detected by the Kaiser test for free amine; however, couplings showed no significant improvement even upon repeated or prolonged reaction. Efficient reactions are known to occur within a fully solvated peptide-polymer matrix, where reagent penetration is rapid and unhindered. This optimal situation no longer exists during the assembly of a difficult peptide, where the normally accessible solid phase reaction matrix becomes partially inaccessible during assembly. This situation arises suddenly, typically 6-12 residues into the synthesis, and may then persist for a number of cycles before easing, or in extreme cases remain throughout the completion of the assembly. The crude products are particularly poor if slower coupling β-branched residues (isoleucine, valine, threonine) are introduced after the onset of synthetic difficulties. The principles underlying the occurrence of difficult peptide sequences have for many years been the focus of intense debate and research. An intrinsic feature of the numerous ideas proposed is that aggregation occurs resulting in poor solvation within the peptide-polymer matrix.