Cerebral cavernous malformations (CCMs) are vasculature defects that can affect the central nervous system with life-threatening consequences such as strokes or seizures. CCMs are observed in conjunction with an irregular, weak capillary network that lacks proper endothelial layers and subendothelial matrix. A large fraction of CCM-associated mutations arise within the CCM1 gene that encodes KRIT1, a protein whose function is not well understood. KRIT1's ability to bind the integrin cytoplasmic associated protein-1 (ICAP1)—which interacts with the cytoplasmic tail of β1-integrin and prevents binding and activation by Talin and Kindlin—suggests a connection between CCMs and defects in cell-adhesion control. Association with KRIT1 prevents ICAP1 binding to β1-integrin and therefore indirectly promotes integrin activation. The molecular details of the interactions between KRIT1 and ICAP1 are now illuminated by crystal structures of the KRIT1–ICAP1 and β1-integrin–ICAP1 complexes, reported by Boggon and colleagues. Although the N-terminal region of KRIT1 on its own evaded crystallization, coexpression with the predicted PTB domain of ICAP1 allowed structural analysis of the complex, which revealed that the N terminus of the KRIT1 folds as a Nudix domain, something not predicted from its primary sequence. The interaction surface between KRIT1 and ICAP1 is composed of two distinct sites, one being a canonical NPxY-PTB interaction. The second interaction site was unanticipated, but the involved residues on both KRIT1 and ICAP1 are evolutionarily conserved, which points to the likely importance of this interface. Turning to the ICAP1–β1-integrin complex, the β1 tail is seen to bind ICAP1 in the canonical PTB-binding site, consistent with KRIT1 directly competing with β1-integrin for ICAP1 association, a point that is clearly demonstrated by functional analyses. In sum, this study provides a mechanistic understanding of how inactivation of KRIT1, commonly observed in association with CCMs, can result in improper integrin activation, which in turn may contribute to a leaky vasculature. (Mol. Cell doi:10.1016/j.molcel.2012.12.005, published online 10 January 2013)