Trans-cellular migration, the movement of one cell directly through another, seems an unlikely, counterintuitive, and even bizarre process. Trans-cellular migration has been reported for nearly half a century in leukocyte transendothelial migration in vivo, but is not well enough accepted to widely feature in textbook accounts of diapedesis. Recently, the first in vitro and additional in vivo observations of trans-cellular diapedesis have been reported. Mechanisms by which this occurs are just beginning to be elucidated and point to podosome-like protrusive activities in leukocytes and specific fusogenic functions in endothelial cells. Emerging evidence for a quantitatively significant contribution of trans-cellular migration to leukocyte trafficking in increasingly diverse settings suggests that this phenomenon represents an important and physiologic cell biological process.