The development and application of biomarkers to neurodegenerative diseases has become increasingly important in clinical practice and therapeutic trials. While substantial progress has been made at the basic science level in understanding the pathophysiology of HIV-Associated Neurocognitive Disorders (HAND), there are significant limitations in our current ability to predict the onset or trajectory of disease, and to accurately determine the effects of therapeutic interventions. Thus, the development of objective biomarkers is critical to further our understanding and treatment of HAND. In recent years, biomarker discovery efforts have largely been driven forward through the implementation of multiple "omics" approaches that include (but are not restricted to): Lipidomics, proteomics, metabolomics, genomics, transcriptomics, and advances in brain imaging approaches such as functional connectomics. In this paper we summarize our progress to date on lipidomic approaches to biomarker discovery, discuss how these data have influenced basic research on the neuropathology of HAND, and implications for the development of therapeutics that target metabolic pathways involved in lipid handling.