Differential integrin expression allows directed migration of T cells along the endothelium, which can occur with (downstream migration) or against (upstream migration) the direction of shear flow. The T cell integrins LFA-1 (αLβ2) and VLA-4 (α4β1) bind to the integrin ligands ICAM-1 and VCAM-1, respectively. VCAM-1 is linked to downstream migration, whereas ICAM-1 supports upstream migration, but the signalling mechanisms resulting in this differential response are still not fully characterised. Building on their previous work, Janis Burkhardt and colleagues (Roy et al., 2020) now identify the signalling outcomes that distinguish LFA-1- from VLA-4-mediated T cell migration under shear flow. In response to LFA-1 engagement, mouse T cells display a broad leading edge with sustained actin polymerisation, which drives migration against shear flow on ICAM-1-covered surfaces; by contrast, on VCAM-1, VLA-4 ligation results in more elongated T cells with only transient flares of F-actin, and promotes downstream migration. Both LFA-1 and VLA-4 activate the phosphoinositide 3-kinase (PI3K) and ERK pathways, but only LFA-1 ligation leads to the phosphorylation of the ubiquitin ligase cCbl. Most importantly, knocking out cCbl or the Crk family of adaptor proteins, which was previously shown to be involved in LFA-1 signalling and cCbl regulation, inhibits upstream migration on ICAM-1. This study uncovers how differential integrin signalling can affect migratory behaviour and identifies Crk and cCbl as key molecules for upstream T cell migration.