When pathogenic or non-pathogenic bacteria colonize surfaces or host tissues they rapidly change their behavior and develop surface-based motility, express virulence traits and eventually mature into multi-cellular communities, called biofilms. Biofilms are difficult to eradicate in the host as they feature in-creased drug resistance and persister rates and provide tolerance against phagocytic clearance. In the past years, c-di-GMP (cdG) was identified as a key regulator of bacterial surface colonization and biofilm for-mation. This provides an opportunity for pharmacological intervention with clinically problematic forms of bacterial growth. Here we analyze the role of cdG signaling in the initial steps of surface colonization and biofilm formation in several bacterial model organisms. We address how bacteria perceive mechani-cal stimuli and how such cues are transmitted into rapid and robust changes in cell behavior including surface-based motility, attachment and expression of virulence factors.