• The N-terminus of GIP is essential for receptor activation. • The C-terminus of GIP has no apparent interaction with the GIP receptor. • C-terminal modifications of GIP has a minimal effect on receptor activation. • The absence of the c-terminus of GIP improves the antagonistic action for the GIP receptor. Enzymatic cleavage of endogenous peptides is a commonly used principle to initiate, modulate and terminate action for instance among cytokines and peptide hormones. The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and the related hormone glucagon-like peptide-2 (GLP-2) are all rapidly N-terminally truncated with severe loss of intrinsic activity. The most abundant circulating form of full length GIP(1–42) is GIP(3–42) (a dipeptidyl peptidase-4 (DPP-4) product). GIP(1–30)NH 2 is another active form resulting from prohormone convertase 2 (PC2) cleavage of proGIP. Like GIP(1–42), GIP(1–30)NH 2 is a substrate for DPP-4 generating GIP(3–30)NH 2 which, compared to GIP(3–42), binds with higher affinity and very efficiently inhibits GIP receptor (GIPR) activity with no intrinsic activity. Here, we review the action of these four and multiple other N- and C-terminally truncated forms of GIP with an emphasis on molecular pharmacology, i.e. ligand binding, subsequent receptor activation and desensitization. Our overall conclusion is that the N-terminus is essential for receptor activation as GIP N-terminal truncation leads to decreased/lost intrinsic activity and antagonism (similar to GLP-1 and GLP-2), whereas the C-terminal extension of GIP(1–42), as compared to GLP-1, GLP-2 and glucagon (29–33 amino acids), has no apparent impact on the GIPR in vitro, but may play a role for other properties such as stability and tissue distribution. A deeper understanding of the molecular interaction of naturally occurring and designed GIP-based peptides, and their impact in vivo, may contribute to a future therapeutic targeting of the GIP system – either with agonists or with antagonists, or both. [ABSTRACT FROM AUTHOR]