Significant new insights are being made into tick modulation of host immune defenses and the implications of those host defense changes on tick-borne pathogen transmission and establishment of infection. Understanding tick saliva complexity increased with construction and analyses of salivary gland cDNA libraries. High throughput next generation sequencing and advances in proteomics are revealing greater complexity of saliva, nature of gene families and differential gene expression patterns not previously attainable. Combined use of genome arrays and histopathology are defining cutaneous gene expression during the course of infestation with pathogen-free ticks and during infestations with ticks experimentally infected with a tick-borne pathogen. Large data sets are being generated that are of value to researchers. A major challenge remains in linking saliva molecules with specific functions. Systems biology technologies provide the tools for analyses of complex tick-host-pathogen interactions that are the underpinnings for development of novel control strategies for ticks and tick-borne diseases of medical and veterinary public health importance.