The term prenylation defines the post-translational modification of proteins consisting of the attachment of lipid isoprenoid residues to the structure of the newly synthesized proteins, enabling their function. Among prenylation targets, Rho GTPases represent key molecular switches operating to maintain cytoskeleton dynamics and, thereby, control cell proliferation, migration, differentiation and cell cycle. Thus, regulation of Rho protein function via prenylation represents a crucial molecular event for the biology of different cell types within the gut mucosa. Our research might help to decipher key pathways and understand the molecular mechanisms involved in the breakdown of intestinal homeostasis in the context of chronic intestinal inflammation and colorectal cancer.