Metabolites are important signaling molecules mediating plant-microbe interaction in soil. Plant root exudates are composed of primary metabolites, secondary metabolites, and macro-molecules such as organic acids. Certain organic acids in root exudates can attract pathogenic microbes in soil and promote infection. Meanwhile, secretions from soil microbes can also alter the compositions of root exudates and enhance the pathogenicity towards the target host plant. Examples of toxins in microbial secretions include polyketides and thaxtomins. The pathogenicity of plant microbes is mediated by the dynamic exchange of metabolites between the pathogen and the host plant. By deciphering this metabolite-mediated infection process, targeted strategies can be developed to promote plant resistance to soil pathogens. Examples of the strategies include the manipulation of root exudate composition and the blocking of metabolite signals that promote microbial infection. Other possibilities include minimizing the harmfulness of pathogenic microbial secretions to plants by habituating the plants to the toxin, genetically engineering plants to enhance their pathogen resistance, and treating plants with beneficial hormones and microbes. In this review, we summarized the current understanding of root exudates and soil microbe secretions that promote infection. We also discussed the strategies for promoting pathogen resistance in plants by focusing on the metabolite signaling between plants and pathogenic soil microbes.