A recent study by Hermosilla et al. [T. Hermosilla, D. Munoz, R. Herrera-Molina, A. Valdivia, N. Munoz, S.U. Nham, P. Schneider, K. Burridge, A.F. Quest, L. Leyton, Direct Thy-1/alphaVbeta3 integrin interaction mediates neuron to astrocyte communication, Biochim Biophys Acta 1783 (2008) 1111-1120] demonstrates that Thy-1 on neurons binds to alphavbeta3 integrin on astrocytes via a conserved RLD motif, triggering the formation of focal adhesions and stress fibers via tyrosine phosphorylation and RhoA activation. This study adds to growing evidence regarding the signaling mechanisms and biological roles of Thy-1, an important regulator of context-dependent signaling. As knowledge of Thy-1 approaches its fiftieth year, it is critical to begin to synthesize insights from different fields to determine how this heretofore enigmatic molecule modulates cell behavior in both cis and trans.