In the past 30 years, the use of fluoroquinolones in veterinary medicine has increased. Due to their efficacy against bacterial infections, good owner compliance, and drug safety profile, fluoroquinolones have been widely used in small animal medicine. The goal of the present article is to review the most updated information on the use of fluoroquinolones in canine pyoderma as second-tier antibiotics based on bacterial culture and susceptibility results. Antibiotic resistance is a very relevant topic in both human and veterinary medicine. It is, therefore, important to make a more responsible selection and use of antibiotics in the course of antimicrobial therapy. In order to promote a rational and prudent use of antibiotics, the aim of this review is to provide clinicians with useful information about the choice of this class of antimicrobial agents for treatment of canine pyoderma.