LSP1 is an F-actin bundling cytoskeletal protein expressed in hematopoietic lineage and endothelial cells. We investigated the function of this protein by generating and analyzing an LSP1-deficient mouse strain and in this review we describe our findings together with those of other investigators. The results show a complex function of LSP1 in regulating leukocyte recruitment to inflamed sites. Based on current evidence, we propose that the levels of LSP1 on the cytoskeleton and the type of integrin involved are some of the critical elements which affect LSP1 function in modulating the threshold for transmigration.