Soil salinization, driven by geogenic processes and anthropogenic activities, poses a critical threat to global agricultural productivity, food security, and ecosystem stability. Affecting over 830 million hectares of land worldwide, salinity disrupts plant physiology through hyperosmotic stress, ionic toxicity, and oxidative damage, disproportionately impacting arid, semi-arid, and coastal regions. Traditional remediation strategies, such as chemical amendments and leaching, are often economically unsustainable and ecologically detrimental. In contrast, biosaline agriculture, centered on phytodesalination using salt-tolerant halophytes, offers a scalable, eco-friendly solution to reclaim degraded soils while supporting resource-efficient food and bioenergy production. This chapter explores the domestication of non-conventional, salt-accumulating plants, with a focus on the genus Pennisetum, as dual-purpose tools for soil rehabilitation and sustainable land use. Halophytes, representing <1% of global flora, exhibit unique adaptations such as osmotic adjustment via proline and glycine betaine, ion compartmentalization through SOS1 and NHX transporters, and salt excretion via specialized glands. The genus Pennisetum (Poaceae family), including economically vital species like P. glaucum (pearl millet) and P. giganteum (Giant Juncao), exemplifies the integration of phytodesalination with agro-industrial valorization. Tolerant of marginal saline soils, Pennisetum species enhance soil structure, yield biomass for fodder and bioenergy, and produce phytochemicals with medicinal applications. Their C4 photosynthetic efficiency and genetic plasticity position them as keystones for sustainable intensification in climate-vulnerable regions. By synthesizing agronomy, soil science, and biotechnology, this work advocates for multidisciplinary frameworks to scale biosaline systems. Prioritizing non-conventional salt accumulating plants/halophyte domestication, farmer-centric policies, and genetic innovation can transform saline landscapes into productive agroecosystems, aligning with global goals for food security and ecological resilience. This paradigm shift, from salinity mitigation to resource utilization, heralds a new era in sustainable agriculture, offering scalable solutions for the twenty-first century’s intertwined climatic and socio-economic challenges.