Plants have been associated with microflora for more than 400 million years, and this long-standing interconnection takes place in different regions of the plants. The complex community of microbes can be beneficial or pose a threat as pathogens. Previous studies have investigated plant immune responses and interactions with diverse microbes however, several aspects remain unclear and require further exploration. Plants utilize several small molecules through their associated biochemical pathways to aid this recognition process. This review examines recent progress on the distinct signaling pathways of various plant small molecules, including amino acids, lipids, and plant secondary metabolites, as well as the receptor-like kinases engaged in recruiting and scrutinizing the microbes involved in interactions. This review additionally explores how the rhizosphere and phyllosphere interact to shape the microbiome, facilitating plant homeostasis. Furthermore, it highlights the remarkable similarities between markets in human societies and those found in microbe–plant biological systems. Together, these ideas offer a framework for understanding how plants interact with advantageous microorganisms while simultaneously limiting harmful pathogens. The specific biochemical mechanisms and their interconnections are gradually being elucidated, providing a potential foundation for the development of novel plant protection strategies. With a holistic approach, these plant‒microbe interactions can be exploited to engineer plants with multiomics approaches for improved performance, which can enhance crop resilience, promote sustainable agriculture, and address global food security in the long term.