There is growing interest in developing strategies to quantify newly identified substances in environmental samples where reference standards are lacking. The newly emerged field of quantitative non-target screening (q-NTS) has gained confidence due to its recent success in accurately measuring the ionization efficiency of substances in various ionization sources. q-NTS provides a semi-quantitative analysis that can assist in the risk assessment of chemicals and their environmental fate. In this chapter, all strategies to derive semi-quantitative analysis in environmental samples were briefly discussed. These strategies included (1) chemical structure similarity; (2) chemical property similarity; (3) chemical derivatization; (4) maximum common substructure overlap; (5) co-eluting analytes; (6) parent compounds versus transformation products; and (7) quantitative ionization efficiency model. For each strategy, its practical implementation in environmental samples, advantages, and disadvantages were comprehensively discussed. In addition, the effect of the analytical method on the accuracy of q-NTS, especially in the case of the quantitative ionization efficiency model, is examined. The possibility of integrating these semi-quantitative analyses into non-target screening is evaluated, and a q-NTS workflow is proposed.