A common property amongst angiogenic ligands such as the vascular endothelial growth factors and the angiopoietins is that they can elicit multiple responses depending upon the context of their expression and the presence of other growth factors. Study of the signal transduction pathways initiated by these growth factors provides insight into the molecular and cellular mechanisms that regulate vessel assembly. Key components of signal transduction cascades can then be used as potential targets in angiogenic therapies. This commentary reviews the recent advances into understanding the molecular signaling pathways mediated through the angiopoietin receptor, Tek/Tie2, as well as their effect on the regulation of distinct cellular aspects of angiogenesis.