The development of solid-phase peptide synthesis by Bruce Merrifield paved the way for a synthesis carried out by machines. Automated peptide synthesis is a fast and convenient way of synthesizing many peptides simultaneously. This chapter tries to give a general guidance for the development of synthesis protocols for the peptide synthesizer. It also provides some suggestions for the modification of the synthesized peptides. Additionally, many examples of possible challenges during and after the synthesis are given in order to support the reader in finding the best synthesis strategy. Numerous references are given to many of the described matters.