Transient Receptor Potential Vanilloid (TRPV) channels are a subfamily of six membrane proteins involved in various physiological processes. TRPVs share a pore channel between the fifth and sixth domains, which can be activated or inactivated by temperature, pain, and cellular homeostasis. Dysregulation of TRPVs can lead to pain, inflammation, and numerous pathological conditions. Understanding the molecular mechanisms that control TRPV channel activation/inhibition, gating, and interactions with ligands is crucial for targeted drug design. Molecular dynamics (MD) simulations have emerged as a powerful computational tool to study TRPVs’ function and ligand interaction. In this chapter, we review the use of MD and other computational tools to investigate the function and gating mechanism of TRPVs, as well as the binding of lipids and small molecules in these channels. In short, we describe the changes induced by channel opening caused by temperature and upon ligand or lipid binding. Furthermore, we review the studies that delve into describing binding sites or discovering new TRPV channel modulators.