As noted above, when it comes to the architecture of proteins, “form follows function.” Thus it is essential that a polypeptide be synthesized with the proper amino acid sequence, and that it fold into the proper three-dimensional conformation, with the appropriate secondary, tertiary, and possibly quaternary structure, if it is to fulfill its biological role within or outside cells. How is a protein with a proper sequence generated? A polypeptide chain is synthesized by a complex process called translation, which occurs in the cytoplasm on a large protein–nucleic acid complex called a ribosome. During translation, a sequence of messenger RNA (mRNA) serves as a template for the assembly of a corresponding amino acid sequence. The mRNA is initially generated by a process called transcription, whereby a nucleotide sequence in DNA is converted, by transcriptional machinery in the nucleus, into a sequence of mRNA. The intricacies of transcription and translation are considered in Chapter 5. Here we describe the key determinants of the proper folding of a newly formed or forming (nascent) polypeptide chain as it emerges from the ribosome.