Non-target screening (NTS) approaches in combination with high-resolution mass spectrometry (HRMS) instrumental arrays have the potential to revolutionize the capabilities of environmental analytical chemistry regarding the identification of transformation products of organic contaminants. The most influential integral parts of the NTS procedure are the selection of the most beneficial data acquisition mode, the optimization of the data processing workflow, the selection of the most appropriate algorithms, and the adoption of the most efficient software tools. The reliability of NTS processes and the avoidance of false positives or negative findings are also important aspects that should be comprehensively considered and may be addressed through standardized protocols, novel filters, and widely accepted evaluation approaches. All these matters together with the enrichment of databases are fundamental to ameliorating the accuracy, effectiveness, applicability, acceptance, and reliability of non-target strategies. This chapter presents a brief overview of NTS strategies for identifying TPs of organic contaminants in environmental matrices following HRMS analysis, highlighting the applied data processing workflows.