Many pathogenic bacteria can form biofilms in clinical settings with major consequences for the progression of infections. Bacterial biofilm communities are typically much more resistant to both antibiotic treatment and clearance by the immune system in comparison to free-living cells. Therefore, drugs that specifically target the formation or maintenance of biofilms would be very valuable additions to current clinical options. Cyclic nucleotide second messengers, in particular cyclic-diguanosine-GMP (c-di-GMP), are now known to play a major role in biofilm formation, and maintenance, in many bacterial species. In this special report, we will review recent progress toward the development of drugs that interfere with c-di-GMP signaling as a route to control biofilm infections. We will focus on the chronic infections associated with the notorious opportunistic pathogen Pseudomonas aeruginosa, although the principles outlined here are also relevant to most bacterial pathogens.