The Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) method is a simple and straightforward extraction technique involving an initial partitioning followed by an extract clean-up using dispersive solid-phase extraction (d-SPE). Originally, the QuEChERS approach was developed for recovering pesticide residues from fruits and vegetables, but rapidly gained popularity in the comprehensive isolation of analytes from different matrices. According to PubMed, since its development in 2003 up to November 2018, about 1360 papers have been published reporting QuEChERS as extraction method. Several papers have reported different improvements and modifications to the original QuEChERS protocol to ensure more efficient extractions of pH-dependent analytes and to minimize the degradation of labile analytes. This analytical approach shows several advantages over traditional extraction techniques, requiring low sample and solvent volumes, as well as less time for sample preparation. Furthermore, most of the published studies show that the QuEChERS protocol provides higher recovery rate and a better analytical performance than conventional extraction procedures. This review proposes an updated overview of the most recent developments and applications of QuEChERS beyond its original application to pesticides, mycotoxins, veterinary drugs and pharmaceuticals, forensic analysis, drugs of abuse and environmental contaminants. Their pros and cons will be discussed, considering the factors influencing the extraction efficiency. Whenever possible, the performance of the QuEChERS is compared to other extraction approaches. In addition to the evolution of this technique, changes and improvements to the original method are discussed.