Many immune responses are dependent on the four members of the leukocyte integrin family of surface receptors. Organ transplantation triggers a range of immune responses aimed at rejecting the donor tissue. Engagement of cells of the immune system including T cells, B cells, and antigen presenting cells with each other or with the donor organ is an essential element of the rejection cascade, and this engagement is mediated by adhesions through the leukocyte integrins and their ligands. This review will first focus on the molecular mechanisms that regulate rapid activation of the leukocyte integrins by inside-out signaling that results in changes in receptor clustering on the leukocyte membrane and ligand affinity. Longer lasting changes in receptor expression through transcriptional mechanisms will also be discussed. The role of these receptors in organ transplant rejection, graft-versus-host disease, and ischemic reperfusion injury will also be reviewed. The potential of anti-adhesion therapy to prolong organ transplant survival will be discussed in both animal and patient studies.