Proper characterization of some environmental, agronomic and industrial samples is still an analytical challenge. New pollutants and sample matrices have put pressure in analytical laboratories for the development of reliable methods that may be used in routine basis. In this context, it is interesting to mention the incorporation of new screening or quantitative low-cost analytical tools to solve analytical problems in the frame of the principles of green analytical chemistry. X-ray fluorescence (XRF) is a well-established analytical technique, which allows the analysis of solid samples with a minimum sample treatment, and recently, its application capability has been boosted up with chemometrics for quantification, classification, and identification of origin. It is interesting to remark that with the use of chemometric tools, the analytical performance of XRF may be also improved including the determination of trace elements by portable XRF systems or the determination of light elements. A myriad of studies utilizing chemometrics and XRF have been recently reported in the literature and in this chapter a comprehensive overview of them will be displayed. The combination of XRF with chemometrics is undoubtedly a field of worth investigation which may open new interesting applications of XRF in many different fields in the near future.