The immune system plays a critical role in protecting humans from both microbes and assaults from our own cells and antibodies. When immune responses become excessive, autoimmune and inflammatory diseases arise; and the pathogenesis of many of these diseases remains obscure. Gene expression profiling allows us to measure the expression of genes at the genome-wide level. We have used this approach to shed light on the mechanisms underlying a diverse group of immune-mediated diseases. To interpret the large amount of data obtained through the application of these techniques, we have developed a series of bioinformatics and statistical tools. Using these approaches and tools, we have explored the role of plasmacytoid dendritic cells in human Systemic Lupus Erythematosus, as well as the effect of therapy on the universal IFN signature that characterizes these patients. In addition, we have analyzed blood gene expression signatures in patients infected with M. tuberculosis, in monogenic and polygenic autoinflammatory diseases, as well as in sporadic diseases that cause cardiovascular inflammation in children. Clues into either pathogenesis and/or unique disease biomarkers have been obtained in each case. We believe that the findings resulting from these studies will enable us to develop specific and robust tests and/or novel therapies that will improve the lives of patients affected by these diseases.