Normal and transformed cells are homing from the circulation into tissues in a very selective way thanks to highly complex molecular mechanisms that govern cell-to-cell interactions and drive the homing of circulating cells to be achieved properly. Because this is characterised by a resulting high selectivity, it constitutes a template for targeted drug-, gene- or cell-therapy strategies. Designing a mimetic-based therapy requires the identification of the responsible selective molecules but also, their mechanisms of action and interactions with their ligands, together with their biological modulation and regulation. This homing/invasion event happens to be decisive at the level of the endothelium that lines the vessel walls. Since cell-to-cell interactions mean a double recognition process, this review will illustrate the part played by the endothelial cells (EC) and their adhesion molecules: the protein as well as the glycan part point of view, the chronology and environmental modulation of EC adhesion molecules expression. These characteristics should provide keys to understand the resulting overall specificity of cell localisation. Taking into account the cytokine microenvironment, it was recently documented a fundamental role for locally secreted chemokines which act through their restricted presentation by endothelial cells. As such, chemokines contribute to illustrate the concept of endothelial organo-specificity which is approached here uncovering the role of glycoconjugates signalling as the hallmark of refined cellular recognitions and discussed, in the context of potential drug design against site-directed diseases as metastases, inflammatory leukocytes recruitment, tumour/inflammation-induced angiogenesis.