The invention provides a method and system for performing computational subtraction to detect microbes within a host organism. In some aspects, the microbes are pathogens and the system is used to identify sequences belonging to these pathogens which can then be used in methods of diagnosis and treatment. Alternatively, the microbes can be symbiotic organisms, such as commensal or parasitic organisms. Preferably, candidate sequences identified as belonging to a microbe are used to isolate and clone additional sequences from the microbe.