The field of infectious diseases is witnessing the rapid evolution of molecular diagnostics, mostly focused on pathogen detection. However, targeting the host response for diagnostic and prognostic purposes has been described as a paradigm shift (Ramilo & Mejias, 2009). The concept of host response is not new. The erythrocyte sedimentation rate described in 1917 and C-reactive protein in 1930 are still used today albeit with limitations. More contemporary biomarkers based on known biology include procalcitonin, cytokines, and lactate. However, completion of the Human Genome Project in 2003 triggered the rapid pace of discovery we see today. This has set the stage for various 'omic technologies to identify new biomarkers from these unbiased systems biology approaches. The massive streams of data associated with omics impose their own challenges, spurring developments in statistics, bioinformatics, and computing. Fortunately, the availability of data and the means to process it have converged, creating the right environment for host-based molecular diagnostics in infectious diseases to flourish. Transcriptomics, metabolomics, and proteomics constitute the major tools to identify host-response biomarkers of infectious diseases. Specifically, research generated by these approaches has led to the development of bacterial, viral, fungal, and parasite pathogen class diagnostic and prognostic biomarkers.