The current revolution in biology especially genomics and proteomics, has identified genes encoding for new biological toxins and super-antigens. There is growing concern within both scientific defense and intelligence communities that this constitutes a serious potential for misuse as offensive biological weapons. Currently, sequences of close to 50 microbial genomes have been completed and the sequences of more than 100 genomes should be completed within the next 2 to 5 years. These sequences will encode a collection of >200,000 predicted coding sequences which will code for important functional proteins, as well as potential new biological toxins and super-antigens. Completed sequences of microbial genomes provide an excellent source to study the physiology and evolution of microbial species and expands our ability to better assign functions to the newly predicted coding sequences. Comparative analysis of sequences for multiple genomes will provide substantially more information on the emerging and re-emerging new biological toxins and super-antigens, and this information will be very valuable in the discovery of new signature sequences to enhance bio-detection, protection and treatment. A model comparative analysis using the complete genome sequence of an M1 strain of Streptococcus pyogenes, also known as group A streptococci (GAS) which is a strict human pathogen with no other known reservoir pr affected species will be discussed.