G protein-gated inwardly rectifying potassium channels (Kir3/GirK) are important for maintaining resting membrane potential, cell excitability and inhibitory neurotransmission. Coupled to numerous G protein-coupled receptors (GPCRs), they mediate the effects of many neurotransmitters, neuromodulators and hormones contributing to the general homeostasis and particular synaptic plasticity processes, learning, memory and pain signaling. Here, we integrate recent findings on the physiology, function, dysfunction, and pharmacology of GirK channels in the central nervous system and highlight the relevance of GirK channels as a worthful potential target to improve therapies for related diseases. A search for articles on PubMed and Google Scholar was performed, using relevant search terms. GirK channels are assembled in a tetrameric unit, conformed by four essential subunits. They are broadly distributed in the central nervous system and have different expression patterns in different neurons and subcellular compartments. GirK channels are downstream targets for various neurotransmitters acting at respective GPCR: GABAB, adenosine A1, 5HT1A, endocannabinoid CB1, D1 and D2-like and other receptors. Although many natural compounds and well-known drugs are found to modulate GirK channels, only few selective agents have been discovered. Behavioral and genetic studies suggest a critical role for the appropriate functioning of the central nervous system and excitatory-inhibitory balance maintenance, as well as their involvement in many neurologic and psychiatric conditions, such as Parkinson and Alzheimer’s diseases, epilepsy, mood disorders, attention deficit hyperactivity disorder, schizophrenia, alcoholism and drug addiction. GirK channels emerge as a very promising tool to be targeted in the current scenario where these conditions already are or will become a global public health problem.