The use of protective clothing, whether in space suits, hazardous waste disposal, or sporting equipment, generally increases the risk of heat stress and hyperthermia by impairing the capacity for evaporative heat exchange from the body to the environment. To date the most efficient method of microclimate cooling underneath protective clothing has been via conductive heat exchange from circulating cooling fluid next to the skin. In order to make the use of liquid microclimate cooling systems ((LQ)MCSs) as portable and practical as possible, the physiological and biomedical engineering design goals should be towards maximizing the efficiency of cooling to maintain thermal comfort/neutrality with the least cooling possible to minimize coolant and power requirements. Meeting these conditions is an extremely complex task that requires designing for a plethora of different factors. The optimal fitting of the (LQ)MCSs, along with placement and design of tubing and control of cooling, appear to be key avenues towards maximizing efficiency of heat exchange. We review the history and major design constraints of (LQ)MCSs, the basic principles of human thermoregulation underneath protective clothing, and explore potential areas of research into tubing/fabric technology, coolant distribution, and control optimization that may enhance the efficiency of (LQ)MCSs.