This chapter discusses the known mechanisms by which cell cycle proteins regulate viability, which of these mechanisms are at play in regulating neuronal viability, evidence that cell cycle regulators are stimulated in HIV encephalitis, the implications of these findings in the post-HAART era, and their potential for additional therapy. The three cell cycle proteins implicated in regulating cell viability are retinoblastoma (pRb), E2F1, and p53. pRb and p53 are the two key targets of signaling pathways that regulate cellular decisions to divide, differentiate, or die. Phosphorylation of pRb has been observed in several in vitro models of neuronal apoptosis including trophic factor withdrawal, DNA damage, low potassium levels, beta-amyloid treatment, and oxidative stress. Further investigation is necessary to determine if they are the ultimate targets for deciding between life and death in neurons for the subset of toxins associated with neurodegeneration in response to HIV encephalitis (HIVE). Investigation into cell cycle proteins in HIVE is still in its early days; however, research thus far indicates that mechanisms of neuronal response to the degenerative stimuli in HIVE are similar to those seen in other neurodegenerative diseases. By understanding the impact of macrophage-secreted factors such as cytokines, chemokines, neurotrophic factors (NTF), and reactive oxygen species (ROS) on modulation of cell cycle regulatory proteins in neurons, a greater insight into neurodegenerative processes in HIVE and neurodegeneration as a whole can be gained and hopefully potential therapeutic targets for treatment of these devastating diseases can be identified.