Bovine viral diarrhea infections are seen in all ages and breeds of cattle worldwide and have significant economic impact due to the productive and reproductive losses. The infectious agents that cause this disease, Bovine viral diarrhea viruses (BVDVs) may occur as two biotypes, of which one is non-cytopathic (ncp) and the other cytopathic (cp), classified according to whether or not they produce visible changes in cell culture. Cytopathic biotypes of BVDV can be created through internal deletion or recombination of RNA of ncp biotypes. The mechanisms of this change are not sufficiently understood. In this review, we discuss the work that has been done to date in our laboratory using methods of proteomics, cellular and molecular biology, and immunology. We found that both biotypes cause numerous changes in the expression levels of the proteins in monocytes, including proteins related to professional antigen presentation, enzymes and receptors, and changes in the infected cell functions related to antigen uptake. However, the alterations caused by the cp and not by the ncp biotypes are consistent with the hypothesis that the virus cytotoxicity involves the mitochondrial dysfunction. Overall, our data show that, the three important signals, antigen-specific, co-stimulatory and cytokine, required to promote the effector activation of naïve T cells to be delivered by professional antigen presenting cells (APCs) are impaired by both types of BVDV. In addition, cp and ncp BVDVs differentially target mitochondrial proteins and antioxidant enzymes that control the fate of infected cells and determine whether BVDVs produce cytopathic effects or replicate noncytopathically to establish persistent infection. This research is aimed to discover foundational knowledge related to host-pathogen interactions and facilitate the development of innovative disease preventatives for pathogens causing significant animal losses.