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The naturally occurring isotope radon-222 (222Rn) is widely employed as a tracer for groundwater discharge to lakes, lagoons, rivers, estuaries, and coastal oceans. Owing to the highly diverse hydrogeological settings, limitations, and assumptions when applying the 222Rn mass balance, there is a clear need to create a uniform approach that will constrain the uncertainties in the reported groundwater fluxes. This review paper provides an overview of the 222Rn measurement techniques and discusses 222Rn mass balances and their application to various hydrological environments. We address the primary uncertainties faced when applying 222Rn mass balances including, (1) atmospheric evasion, (2) groundwater endmember, (3) offshore mixing loss, (4) steady-state assumptions, and (5) upscaling groundwater discharge from 222Rn measurements, and approaches that can be applied to minimize these uncertainties. Finally, we provide guidelines and open-source scripts (i.e., R codes and FINIFLUX) that should assist future studies using 222Rn to quantify groundwater discharge to surface waters.