In recent years, we have been facing a significant increase in antimicrobial resistance and complex enzymatic mechanisms. The challenge of antibiotic resistance is becoming dramatic. Among gram-positive it is spreading resistance to glycopeptides, reducing the possibility to use these drugs empirically. Among gram-negative rods, beside the spreading of extended-spectrum β-lactamases, there is an increased diffusion of carbapenemases. In order to administer the correct antibiotic therapy, physicians need a rapid and correct interpretation with non-automated tests to implement appropriate therapeutic strategies. The automated reporting systems do not always provide complete and accurate information on antimicrobial resistance phenotype, making it difficult to interpret. Recently, the European Committee of Antimicrobial Susceptibility Testing (EUCAST) has proposed a new breakpoint system to be adopted by European countries. An interpretative reading of an antibiogram aims to analyze the overall susceptibility pattern, not just the result for an individual antibiotic, and so to predict the underlying resistance mechanisms. The purpose of this work is to guide physicians in reading and understanding antibiograms through an attempt of phenotypic interpretation of resistance mechanism.