Infectious diseases are one of the leading causes of death in the world. This major medical concern is due to the continual emergence of new infectious diseases and reemergence of old pathogens, together with an increasing number of pathogens resistant to antimicrobial drugs. The generation of new anti-infective agents for resolving these medical problems has emerged as an urgent issue in modern medicine. The availability of genome sequences, and the development of various high-throughput techniques and computational tools offer holistic and integrative strategies for dissecting the interplay between microbial pathogens and their hosts (infectomics). Both microbial and host signatures of infectomes, which mirror the interplay between pathogens and their hosts, provide invaluable fountains in the search for novel antimicrobial therapies. There are several major issues in the discovery and development of new drugs, from target discovery and validation to animal models and clinical trials. However, infectomic approaches integrating genomics, proteomics and glycomics will become increasingly important. Essential Therapeutics Inc. has successfully used functional genomic methods to identify several hundred antimicrobial targets in representative bacterial, fungal and viral pathogens. Recent advances in chemical genomics and proteomics have revolutionized drug discovery research by allowing the parallel processing of multiple genomic targets against large numbers of diverse compounds. The identification of small-molecule modulators of biological functions that are usually executed by large molecules (DNAs, RNAs, proteins and polysaccharides), and the process of transforming these into high-content lead series, are key activities in modern drug discovery. This review focuses on infectomics and its applications to antimicrobial drug discovery.