One of the defining characteristics of HIV is its ability to manipulate the human immune response to promote its own replication. Since the beginning of the epidemic, there has been controversy whether a robust immune response to the virus is beneficial or detrimental for the host. Therefore, the effects of HIV on signaling pathways and cytokine production need to be characterized in order to distinguish between protective immune responses and inappropriate immune activation. Cytokine and biomarker expression during HIV infection results from the combined effects of intracellular signaling pathways orchestrated by kinases like P38 and ERK. The P38 and ERK Mitogen-Activated Protein Kinase (MAPK) pathways govern the regulation of cytokines (IL-2, IL-10, and TNF-α) as well biomarkers (PD-1, Fas/FasL, among others) that are skewed in chronic HIV infection. HIV utilizes the P38 and ERK pathways to produce new virions and to deplete CD4+ T cells from the host's immune system. Understanding the interplay between HIV and the cytokines induced by activation of the P38 and ERK pathways may provide insights into HIV immunopathogenesis and the development of a protective vaccine.