The replacement of the amide bond in a peptide backbone is a promising strategy in peptidomimetic drug research. Over the various amide bond surrogates, the fluoroolefin moiety has been successfully developed as an effective mimic. Today, fluorine-containing compounds account for a large proportion of new active molecules in life sciences. The synthesis of fluoroolefin peptide mimics is not a trivial task and innovative approaches often need to be addressed, in particular for the stereocontrol of the double bond configuration and the chiral centres adjacent to the fluoroalkene. These fluorinated peptidomimetics have been synthesised and evaluated as metabolically stable and/or conformationally constrained analogs of enzyme inhibitors, and as tools for probing the function, structure, and binding process of receptors.