Plants thrive in a complex environment comprising of various biotic and abiotic agents. Like all biological systems, these agents tend to interact with the plant body. Microorganisms form a major portion of the ecosystem and have been found to inoculate or infect members of all the kingdoms. Plants and microbes have developed molecular mechanisms to interact with one another and attain the maximum benefi t from the interactions. This mutualistic relationship provides benefi t not only to the microbes but also to the plants. Based upon this complex molecular interplay, a number of mechanisms have been studied and are currently being employed for the agricultural, environmental, and health benefi ts. The principles of biofertilization and bioremediation utilize the plant-microbe interactions for the survival of the two players along with contributing to the food chain and the ecosystem. Similarly, the secondary metabolites obtained from these organisms contribute to human medical and agricultural welfare. These processes are regulated by a variety of biological, physical, chemical, and environmental factors, the study of which can be helpful in exploiting better outcomes from the interaction. The advent of modern techniques has helped in deciphering the role of various molecular players of the plant-microbe interactions. Moreover, they can be employed for regulating the plant-microbe interaction for improved effi ciency. The current chapter discusses the molecular mechanisms involved in the plant-microbe interactions exhibited in biofertilization, bioremediation, biocontrol, and induced systemic resistance. Afterwards, the factors affecting the molecular machinery involved in these pathways have been discussed. Toward the end, a brief introduction of the genetic 2 manipulative techniques and their applications in the plant-microbe interactions has been presented.