In the pursuit of higher food production and economic growth and increasing population, we have often jeopardized natural resources such as soil, water, vegetation, and biodiversity at an alarming rate. In this process, wider adoption of intensive farming practices, namely changes in land use, imbalanced fertilizer application, minimum addition of organic residue/manure, and non-adoption of site-specific conservation measures, has led to declining in soil health and land degradation in an irreversible manner. In addition, increasing use of pesticides, coupled with soil and water pollution, has led the researchers to search for an environmental-friendly and cost-effective alternatives to controlling soil-borne diseases that are difficult to control, and which significantly limit agricultural productivity. Since the 1960s, disease-suppressive soils (DSS) have been identified and studied around the world.Soil disease suppression is the reduction in the incidence of soil-borne diseases even in the presence of a host plant and inoculum in the soil. The disease-suppressive capacity is mainly attributed to diverse microbial communities present in the soil that could act against soil-borne pathogens in multifaceted ways. The beneficial microorganisms employ some specific functions such as antibiosis, parasitism, competition for resources, and predation. However, there has been increasing evidence on the role of soil abiotic factors that largely influence the disease suppression. The intricate interactions of the soil, plant, and environmental components in a disease triangle make this process complex yet crucial to study to reduce disease incidence. Increasing resistance of the pathogen to presently available chemicals has led to the shift from culturable microbes to unexplored and unculturable microbes. Agricultural management practices such as tillage, fertilization, manures, irrigation, and amendment applications significantly alter the soil physicochemical environment and influence the growth and behaviour of antagonistic microbes. Plant factors such as age, type of crop, and root behaviour of the plant could stimulate or limit the diversity and structure of soil microorganisms in the rhizosphere. Further, identification and in-depth of disease-suppressive soils could lead to the discovery of more beneficial microorganisms with novel anti-microbial and plant promoting traits. To date, several microbial species have been isolated and proposed as key contributors in disease suppression, but the complexities as well as the mechanisms of the microbial and abiotic interactions remain elusive for most of the disease-suppressive soils. Thus, this review critically explores disease-suppressive attributes in soils, mechanisms involved, and biotic and abiotic factors affecting DSS and also briefly reviewing soil microbiome for anti-microbial drugs, in fact, a consequence of DSS phenomenon.