Research into leukocyte trafficking and its therapeutic exploitation appears to be a multistep process, just like the trafficking cascade itself. The initial euphoria evoked by an early understanding of the trafficking steps was followed by considerable disappointment following the clinical failure of the first selectin antagonist Cylexin (CY-1503), a sialyl Lewis(X) mimetic. The research area recovered and identified additional attractive pharmacological targets such as chemokine receptors and integrins. However, after lack of efficacy in anti-chemokine trials and the fatalities associated with anti VLA-4 therapy (Tysabri), the question arose again whether targeting leukocyte trafficking is really promising or whether such a complex, multistep process with many redundant and/or functionally overlapping molecules is simply too challenging to deal with. In this article, we delineate some pros and cons of this approach followed by a brief update on where we stand in the field and where we might move in the future.