Root-knot nematodes (Meloidogyne species) are the most devastating and as such they cause significant yield loss in tomato production. They are widely distributed in major tomato producing areas especially in warm climatic conditions. Because of the environmental impact of the application of pesticides, the use of nematode resistant varieties is becoming the most effective alternative to control root-knot nematodes. Several resistance genes are identified from wild tomato and other species. However, Mi-1 resistance gene is the only well characterized and used in many commercial tomato cultivars. A single dominant gene (Mi-1) with a hypersensitive response (HR), which is characterized by a local cell death at the site of nematode penetration and necrotic lesions of the surrounding tissue controls the resistance. Thus, Mi-1 gene either inhibits the penetration of second juvenile stage (J2), reduces number of gall formation, or reduces further development and reproduction rate of the nematode. However, the gene is a temperature dependent and broken by the virulent pathotypes. Plant growth hormones such as salicylic acid (SA) and jasmonic acid (JA) are involved in induced resistance, which is activated after infection. Secondary plant metabolites including amino acids, phenols, and lipophilic molecules were increased in resistant varieties as defense mechanism. The durability of the Mi-gene is a major concern since the resistance lost at high temperature. Heat stable resistance gene (Mi-9) is identified from Solannum arcanum. Hence, pyramiding of the resistance genes in commercial cultivars and genetic modification of plant metabolites might improve the durability of the gene.