Gastrointestinal (GI) disorders have provided a research area eliciting a lot of interest for the development of peptides as potential therapeutic treatment options. For example, the endogenous gut hormones supporting digestion and the signaling along the gut-brain axis have provided interesting starting points for peptide therapeutics, a subset of which are covered in this review, and have led to a much-improved understanding of the underlying mechanisms of action. Important discoveries have been made for new peptide structures and their pharmacology. However, while providing interesting targets for the treatment of gastrointestinal disorders, the intestinal tract is also unforgiving for peptides, which are typically highly susceptible to degradation at gastrointestinal pH in the presence of local proteases. This mini-review outlines how innovative drug hunters have learned to create analogues of natural hormones or de novo peptides that can withstand the harsh gut environment, at times taking advantage of the therapeutic potential of local receptors in the gut lumen, without the requirement for systemic peptide exposure and the safety concerns that could be associated with it. Rather than providing a systematic discussion for each peptide along a common template, this review focuses on aspects of several peptide development programs, that are particularly noteworthy or intriguing. What all the peptides described in this article have in common is their unique pharmacology, often acting as closely related, improved analogues of endogenous hormones with an important role in gastrointestinal health. For each of the peptides described in this chapter, interesting medicinal chemistry or pharmaceutical development challenges were solved. These are outlined here in addition to the peptides' pharmacology, some insight into the gastrointestinal disorders these peptide therapeutics are designed to treat and some of their clinical success stories.