Tuberculosis is caused by Mycobacterium tuberculosis (Mtb) infection. Mtb is one of the oldest human pathogens, and evolves mechanisms implied in human evolution. The lungs are the first organ exposed to aerosol transmitted Mtb during gaseous exchange. Therefore, the guards of the immune system in the lungs, such as macrophages (Ms) and dendritic cells (DCs), are the most important defense against Mtb infection. There have been several studies discussing the functions of Ms and DCs during Mtb infection, but the genome-wide pathways and networks are still incomplete. Furthermore, the immune response induced by Ms and DCs varies. Therefore, we analyzed the cross-talk genome-wide genetic-and-epigenetic interspecies networks (GWGEINs) between Ms vs. Mtb and DCs vs. Mtb to determine the varying mechanisms of both the host and pathogen as it relates to Ms and DCs during early Mtb infection. First, we performed database mining to construct candidate cross-talk GWGEIN between human cells and Mtb. Then we constructed dynamic models to characterize the molecular mechanisms, including intraspecies gene/microRNA (miRNA) regulation networks (GRNs), intraspecies protein-protein interaction networks (PPINs), and the interspecies PPIN of the cross talk GWGEIN. We applied a system identification method and a system order detection scheme to dynamic models to identify the real cross-talk GWGEINs using the microarray data of Ms, DCs and Mtb. After identifying the real cross-talk GWGEINs, the principal network projection (PNP) method was employed to construct host-pathogen core networks (HPCNs) between MO vs. Mtb and DCs vs. Mtb during infection process. Thus, we investigated the underlying cross-talk mechanisms between the host and the pathogen to determine how the pathogen counteracts host defense mechanisms in M phi s and DOs during Mtb H37Rv early infection. Based on our findings, we propose Rv1675c as a potential drug target because of its important defensive role in Ws. Furthermore, the membrane essential proteins v1098c, and Rv1696 (or cytoplasm for Rv0667), in Mtb could also be potential drug targets because of their important roles in Mtb survival in both cell types. We also propose the drugs Lopinavir, TMC207, ATSM, and GTSM as potential therapeutic treatments for Mtb infection since they target the above potential drug targets.