Salinity is a major abiotic stress factor affecting crop yield worldwide. Significant advances have been made in understanding the molecular basis of plant salinity tolerance, many involving transporter genes governing sodium and/or potassium homeostasis. Salt exclusion has been a premier trait targeted in most crop breeding programmes, utilizing intraspecific variation or trait introgression from close crop wild relatives (CWRs). There is also evidence to suggest that, as a ‘by-product’ of domestication, many crop species have lost naturally existing salt-tolerance traits. In this scenario, salt-tolerant CWRs (primary, secondary, or tertiary gene pools) can be targeted for ‘de novo’ domestication using knowledge-based breeding strategies. Domestication traits in crop species constitute a shared repertoire of phenotypic features. A prerequisite for de novo domestication of CWRs is a pipeline of tools and strategies: availability of a high-quality reference genome, efficient plant transformation processes, information on genes involved in domestication, and the ability to ‘edit’ these genes in the CWR using CRISPR (clustered regularly interspaced short palindromic repeats) or prime editing. Incorporation of focused identification of germplasm (involving CWRs) and rapid generation advancement techniques (speed breeding, CRISPR-Combo) into the above pipeline is also recommended to accelerate development of de novo domesticated CWRs with pre-existing traits for salt tolerance.