Liver sinusoidal endothelial cells (LSECs) are specialised endothelial cells that orchestrate hepatic homeostasis within the liver sinusoid. Besides their key role in regulating intrahepatic vascular tone, trafficking and cellular crosstalk, their scavenging and immune-regulatory role makes them central to the development of liver disease. LSEC dysfunction includes loss of fenestrae, inflammatory activation and the gain of vasoconstrictive and prothrombotic functions. Robust evidence has demonstrated how preserving LSECs is crucial in a pathological context, placing LSECs at the centre of novel therapeutic and diagnostic strategies.