Climate change, water scarcity, and human activities are increasing cultivation in protected areas, usually without proper crop rotation, ultimately leading to unfavorable growing conditions that reduce the profitability of the crop. Tomato (Solanum lycopersicum) is one of the most important and leading horticultural vegetable crops in protected areas. Adverse growing conditions pose a serious threat to plant growth (especially in protected areas) and prevent plants from reaching their genetic potential, reducing yields and threatening food security. Grafting can alleviate the negative impact of unfavorable growing conditions on tomato scions and thus provides an alternative way to maintain fruit yield and quality. Currently, there are several commercial tomato rootstocks, most of them are interspecific hybrids between S. lycopersicum and: S. habrochaites, S. peruvianum, S. pimpinellifolium or S. lycopersicum. Although a number of rootstocks are available at market, there is not enough information related to scion–rootstock compatibility. Using these rootstocks, we cannot solve all current and future production problems. Wild Solanaceae species represent a hidden genetic source that could solve several problems related to the abiotic and biotic stresses in tomato production. Although the scion influences final plant size, yield, and fruit quality in grafted plants, the rootstock(s) can also influence/alter these traits. The effects of wild rootstocks on these parameters are not known. Many of the Solanaceae species are characterized by fruits rich in health-promoting substances. On the other hand, most plants in the Solonaceae family contain alkaloids that are/can be used for pharmaceutical purposes, but can also be negative/toxic to human health. Since not all combinations of scion and rootstock are suitable for further production and consumption, it is necessary that we carefully monitor the morphometric, physio-biochemical and metabolic characteristics of the plants during field trials under control conditions in order to obtain the maximum benefit from grafting/rootstocks for growers and consumers.