AbstractPeptoid oligomers were initially developed as part of a larger basic research effort to accelerate the drug‐discovery process in the biotech/biopharma industry. Their ease of synthesis, stability, and structural similarity to polypeptides made them ideal candidates for the combinatorial discovery of novel peptidomimetic drug candidates. Diverse libraries of short peptoid oligomers provided one of the first demonstrations in the mid‐1990s that high‐affinity ligands to pharmaceutically relevant receptors could be discovered from combinatorial libraries of synthetic compounds. The solid‐phase submonomer method of peptoid synthesis was so efficient and general that it soon became possible to explore the properties of longer polypeptoid chains in a variety of areas beyond drug discovery (e.g., diagnostics, drug delivery, and materials science). Exploration into protein‐mimetic materials soon followed, with the fundamental goal of folding a non‐natural sequence‐specific heteropolymer into defined secondary or tertiary structures. This effort first yielded the peptoid helix and much later the peptoid sheet, both of which are secondary‐structure mimetics that are close relatives to their natural counterparts. These crucial discoveries have brought us closer to building proteinlike structure and function from a non‐natural polymer and have provided great insight into the rules governing polymer and protein folding. The accessibility of peptoid synthesis to chemists and nonchemists alike, along with a lack of information‐rich non‐natural polymers available to study, has led to a rapid growth in the field of peptoid science by many new investigators. This work provides an overview of the initial discovery and early developments in the peptoid field. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 545–555, 2011.