Integrins meditate the interaction between cells and the extracellular environment. Their activity is modulated by intracellular signals that alter the ability of integrins to interact with their respective ligands. But despite more than 20 years of research on integrins, relatively few of their activators and inhibitors have been identified. Here, Johanna Ivaska and colleagues (p. 649) describe a ‘druggable’ genome-wide RNAi screening approach to uncover new regulators of β1 integrin. Using the recently developed cell spot microarray technology in a total of 12 cell lines, they identify 13 activators and 10 inhibitors of β1-integrin activity. They find that many of these regulators are involved in regulating inflammation, and changes in β1-integrin activity can influence invasion of cancer cell in vitro. By investigating an activating (CD9) and an inhibiting (MMP8) protein in more detail, the authors further validate their screen and define specific functions for these two regulators. CD9 associates with β1 integrin and activates ligand binding. By contrast, MMP8, a secreted metalloprotease, binds to the external region of this integrin and, thereby, negatively affects its ability to interact with ligands. Together, these findings support the fact that changes in integrin activity are associated with inflammation and tumour progression, and illustrate how complex the regulation of integrin activity is.