Inflammation causes or accompanies a huge variety of diseases. Migration of leukocytes from the blood into the tissues, in the tissues, and from the tissues to lymphatic vasculature is crucial in the formation and resolution of inflammatory infiltrates. In addition to classical adhesion and activation molecules, several other molecules are known to contribute to the leukocyte traffic. Several of them belong to ectoenzymes, which are cell surface molecules having catalytically active sites outside the cell. We will review here how several ectoenzymes present on leukocytes or endothelial cell surface function as adhesins and/or modulate the extravasation cascade through their enzymatic activities. Moreover, their therapeutic potential as immune modulators in different experimental inflammation models and in clinical trials will be discussed.