New sequencing technologies coupled with comparative genomics and evolutionary analysis are poised to impact our response to infectious disease outbreaks. Sequencing data, if collected in real-time can inform outbreak response efforts. In this talk, I will discuss recent progress in developing a real-time genomics-informed outbreak system as part of the ARTIC collaboration, focused around real-time nanopore sequencing, and talk about the potential and challenges for using culture-independent sequencing-based diagnostics to detect pathogens in outbreaks of unknown disease.