In both human and veterinary medicine, the failure of apparently appropriate antimicrobial therapy is a common and often exasperating clinical problem. There are many factors associated with the failure of antibiotic therapy, including an incorrect diagnosis of infectious disease, selection of the inappropriate antibiotic, and incorrect dosage. To achieve the best results bacteriological diagnostics in the laboratory should be made. Even though the in-vitro antimicrobial susceptibility testing guides the potentially suitable antimicrobials, the in-vitro susceptibility obtained is not always the best in-vivo. The clinician should be aware of other factors, including biofilm-forming bacteria, physicochemical conditions at the site of infection (such as perfusion rate, oxygen partial pressure, and pH value), or immunosuppression of the patient that can lead to failure of the treatment. This review summarized the main factors associated with antibiotic failure in a veterinarian practice. In a world where the animal and human resistance to an antibiotic is rising every year, rational and efficient use of antibiotic therapy is of utmost importance. It is essential to continue with the education of veterinary practitioners in all aspects of antimicrobial resistance and antimicrobial treatment to improve future treatments and have a more rational use of antibiotics to reduce the prevalence of antibiotic resistance in animals and humans.