Urea is the most widely used nitrogen (N) fertilizer, with a projected increase in annual demand of 1.5% in the coming years. After its application to soil, urea undergoes hydrolysis via the urease enzyme, causing increases in the soil pH in the surrounding area of the granules and resulting in NH3 losses that average 16% of N applied worldwide and can reach 40% or more in hot and humid conditions. The use of urease inhibitors is an effective way to reduce NH3 losses. Several compounds act as urease inhibitors, but only N-(n-butyl) thiophosphoric triamide (NBPT) has been used worldwide, being the most successful in a market that has grown 16% per year in the past 10 years. Only in the past three years other compounds are being commercially launched. In comparison to urea, NBPT-treated urea reduces NH3 loss by around 53%. Yield gain by NBPT usage is of the order of 6.0% and varies from -0.8 to 10.2% depending on crop species. Nitrification inhibitors usually increase NH3 volatilization and mixing them with urease inhibitors partially offsets the benefits of the latter in reducing NH3 loss. The efficacy of NBPT to reduce NH3 loss is well documented, but there is a need for further improvement to increase the period of inhibition and the shelf life of NBPT-treated urea.