Leukocyte trafficking serves a critical function in central nervous system (CNS) immune surveillance. However, in many disease states leukocyte entry into the CNS is increased, which can disrupt the blood-brain barrier (BBB) and propagate neuroinflammation. These pathologic processes result in BBB permeability, glial activation, and neuronal compromise, all of which contribute to CNS damage. The resulting neuronal injury and loss are characteristic of many neuroinflammatory conditions including Alzheimer disease, multiple sclerosis, HIV-1 encephalopathy, sepsis, ischemia and reperfusion, and CNS tumors. HIV-1 encephalopathy is unique among these processes in that viral activity exacerbates CNS immune dysregulation and promotes chronic neuroinflammation and neurodegeneration. Thus, a significant number of HIV-1-infected persons exhibit neurocognitive and/or motor impairment. This review discusses the mechanisms that regulate leukocyte recruitment into the CNS and how HIV-1 infection dysregulates this process and contributes to neuropathology. Experimental BBB models to study leukocyte transmigration and the potential of targeting this transmigration across the BBB as a therapeutic strategy are also discussed.