Conventional antimicrobial susceptibility tests, including phenotypic and genotypic methods, are insufficiently accurate and frequently fail to identify effective antibiotics. These methods predominantly select therapies based on the antibiotic response of only the lead bacterial pathogen within pure bacterial culture. However, this neglects the fact that, in the majority of human infections, the lead bacterial pathogens are present as a part of multispecies communities that modulate the response of these lead pathogens to antibiotics and that multiple pathogens can contribute to the infection simultaneously. This discrepancy is a major cause of the failure of antimicrobial susceptibility tests to detect antibiotics that are effective in vivo. This review article provides a comprehensive overview of the factors that are missed by conventional antimicrobial susceptibility tests and it explains how accounting for these methods can aid the development of novel diagnostic approaches.