Phospholipases C beta (PLC-βs) are essential components of the signal transduction of metazoans. They catalyze
the production of the second messengers inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from the hydrolysis
of phosphatidylinositol-4,5-bisphosphate (PIP2). These enzymes are activated by G-protein-coupled receptors
(GPCRs) through the interaction with the alpha subunit of heterotrimeric G-proteins belonging to the Gq family (Gαq), the
Gβγ subunits released by the inhibitory G-protein (Gi) and Ca2+ ions. Here we review current structural insights on these
important proteins, with a particular focus on the most structurally characterized isoform (PLC-β3) and the activation
mechanism operated by Gαq. We propose, following the lead of recent studies, that a tight combination of experiments
and molecular simulations are instrumental in further enlightening the structure/function understanding of PLC-βs.