Molecular diagnostic tests for infectious diseases may be either direct or indirect. Direct tests target pathogen-derived molecules (such as viral antigens or nucleic acids), while indirect tests target host-derived molecules such as antibodies. Direct tests can face problems with fast-evolving pathogens, highly localized infections, or agents that replicate at very low levels. In contrast, antibodies are generally undetectable for the first week of infection, frequently cross react against related pathogens, and cannot easily distinguish current from past infections. There is therefore a constant need for new and better diagnostic tests. Quantitative ‘omics’ including transcriptomics, proteomics and metabolomics are well suited for identification of host-derived biomarkers. The chemical uniformity of RNA makes it a particularly attractive target, and RNA-Seq enables detailed measurement of transcripts over a large dynamic range. One promising category of biomarkers are microRNAs, which exhibit several attractive characteristics: Easy extraction from blood or serum, reduced transcriptional complexity (no splicing and moderate diversity), and each sequencing read corresponds to exactly one count (no need to adjust for transcript length). Despite these advantages, several challenges remain. In particular, microRNA quantification is somewhat platform-dependent. Reasons for this include difficulty with normalization due to skewed sample composition (the single most abundant miRNA can make up > 95% of some samples), and the natural occurrence of isomiRs can influence abundance estimates. Nevertheless, host microRNAs are a promising class of infectious disease biomarkers.