Human immunodeficiency virus Type 1 (HIV-1) infection and associated diseases continue to represent major health problem worldwide. FOXO transcriptional factors play an important role in the regulation of cell apoptosis, cell cycle arrest, stress resistance, metabolism and differentiation. This chapter will discuss the diverse functions of FOXO in different cell types including T-cells, macrophages, neurons and astrocytes within the context of HIV-1 infection. Given the overwhelming evidence that FOXO proteins influence the cell fate of immune cells and involve in the homeostasis of the central nervous system (CNS), we will also discuss the potential role of FOXO factors in HIV-1-associated neurological disorders.