The present invention provides methods and compositions for modulating transendothelial migration (TEM) of leukocytes. In particular, inhibition of TEM can provide a potent therapeutic approach to treating inflammatory conditions. The invention specifically relates to the discovery that the adhesion molecule CD99L2 mediates TEM of leukocytes. CD99L2 is present on endothelial cells and leukocytes and mediates leukocyte-endothelial cell adhesion. Blockade of CD99L2 by use of a specific antibody blocks migration of leukocytes into a site of inflammation. CD99L2 shows functional analogy to the structurally-related molecule, CD99, inhibition of which, in conjunction with inhibition of PECAM, causes near total blockade of TEM. Thus, blocking CD99L2 on either endothelial cells or monocytes can block migration 80-90%. In conjunction with PECAM inhibitors, TEM blockade can approach 100%. Therapeutic treatments involving inhibition of CD99L2 show significant promise in remediation of inflammatory conditions.