Worldwide food security is under threat in the actual scenery of global climate change because the major staple food crops are not adapted to hostile climatic and soil conditions. Significant efforts have been performed to maintain the actual yield of crops, using traditional breeding and innovative molecular techniques to assist them. However, additional strategies are necessary to achieve the future food demand. Clustered regularly interspaced short palindromic repeat/CRISPR-associated protein (CRISPR/Cas) technology, as well as its variants, have emerged as alternatives to transgenic plant breeding. This novelty has helped to accelerate the necessary modifications in major crops to confront the impact of abiotic stress on agriculture systems. This review summarizes the current advances in CRISPR/Cas applications in crops to deal with the main hostile soil conditions, such as drought, flooding and waterlogging, salinity, heavy metals, and nutrient deficiencies. In addition, the potential of extremophytes as a reservoir of new molecular mechanisms for abiotic stress tolerance, as well as their orthologue identification and edition in crops, is shown. Moreover, the future challenges and prospects related to CRISPR/Cas technology issues, legal regulations, and customer acceptance will be discussed.