Negative plant-soil feedbacks play an important role in soil sickness, which is one of the factors limiting the sustainable development of intensive agriculture. Various factors, such as the buildup of pests in the soil, disorder in physico-chemical soil properties, autotoxicity, and other unknown factors may contribute to soil sickness. A range of autotoxins have been identified, and these exhibit their allelopathic potential by influencing cell division, water and ion uptake, dark respiration, ATP synthesis, redox homeostasis, gene expression, and defense responses. Meanwhile, there are great interspecific and intraspecific differences in the uptake and accumulation of autotoxins, which contribute to the specific differences in growth in response to different autotoxins. Importantly, the autotoxins also influence soil microbes and vice versa, leading to an increased or decreased degree of soil sickness. In many cases, autotoxins may enhance soilborne diseases by predisposing the roots to infection by soilborne pathogens through a direct biochemical and physiological effect. Some approaches, such as screening for low autotoxic potential and disease-resistant genotypes, proper rotation and intercropping, proper soil and plant residue management, adoption of resistant plant species as rootstocks, introduction of beneficial microbes, physical removal of phytotoxins, and soil sterilization, are proposed. We discuss the challenges that we are facing and possible approaches to these.