The genus Anaplasma (Rickettsiales: Anaplasmataceae) includes several tick-transmitted pathogens that impact veterinary and human health. Tick-borne pathogens cycle between tick vectors and vertebrate hosts and their interaction is mediated by molecular mechanisms at the tick-pathogen interface. These mechanisms have evolved characteristics that involve traits from both the tick vector and the pathogen to insure their mutual survival. Herein, we review the information obtained from functional genomics and genetic studies to characterize the tick-Anaplasma interface and evolution of A. marginale and A. phagocytophilum. Anaplasma and tick genes and proteins involved in tick-pathogen interactions were characterized. The results of these studies demonstrated that common and Anaplasma species-specific molecular mechanism occur by which pathogen and tick cell gene expression mediates or limits Anaplasma developmental cycle and trafficking through ticks. These results have advanced our understanding of the biology of tick-Anaplasma interactions and have opened new avenues for the development of improved methods for the control of tick infestations and the transmission of tick-borne pathogens.