Just like bacteria need to be mobile to seek for nutrients, bacteria need to adhere to biotic and abiotic surfaces to enable their progression. Most bacteria regulate the expression of a multitude of fimbrial adhesins that display varying specificities and architectures. FimH at the tip of type 1 fimbriae is one of the first recognized lectins on Escherichia coli. FimH evokes through its binding symptomatic and chronic E. coli infections in the urinary tract, in the intestine, and beyond. The mannose specificity of type 1 fimbriae has been the lead to the discovery of the FimH adhesin more than 32 years ago and presents today a role model as the template for anti-adhesive drug design. Curiously, the specificity of the FimH lectin had been defined very early on toward a Manα1,3Manβ1,4GlcNAc trisaccharide isolated from the urine of mannosidase-deficient patients. Indeed, a much larger dependence of bacterial adhesion can be attributed to structural differences in the mannosidic receptors than based on amino acid variance in FimH. The crystal structure of FimH in complex with oligomannoside-3 presented a breakthrough that enhanced the rational design of mannose-based anti-adhesives against FimH. In this overview, we will provide insights gained from a plethora of FimH antagonists. Crystal structures of FimH in complex with anti-adhesives and applications in vivo in mouse models for metabolic diseases reveal unexpected features and alternative routes for improved molecules.