Neurotransmitter-gated ion channels are complex neuroreceptors located in the membrane of nerve cells that control the rapid transmission of nerve impulses. Their malfunction is linked to serious neurological disorders, including Alzheimer’s disease, and they are major therapeutic targets; in invertebrates they are involved in insecticide resistance. However, we have little idea of how they function at the molecular level due to their complexity and limited experimental information. In particular it is not clear how the binding of a small molecule (the neurotransmitter) triggers a series of events culminating into the opening (gating) of the transmembrane channel: ions can then flood across the cell membrane modifying the cell activity. State-of-the-art and novel computational techniques are therefore crucial to build an accurate picture at the atomic level of the mechanisms that drive the activation of these ion channels, complementing the available experimental data. We have used a range of simulation techniques, including metadynamics (a method for accelerating rare events and sample free energy landscapes), to explore the mechanisms of neurotransmitter binding and a potential molecular switch for channel gating. As prototypical examples, we have focussed on the insect GABA-activated RDL receptor and on the serotonin-activated 5-HT3 receptor.