Soil is a complex product of nature’s forces that provides a home for countless organisms and serves as the foundation for agriculture. Soil microorganisms play a pivotal role in enhancing the function and structure of soil ecosystems. In the past century, science has revealed a crucial link between soil productivity and the activity of microorganisms. This chapter explores key groups of these microorganisms—bacteria, fungi, actinomycetes, and nematodes—and highlights their diverse roles in improving soil fertility, with a particular focus on agriculture in Africa. In this chapter, we provide an in-depth overview of the roles of soil microorganisms in soil health and soil nutrient management. We reviewed factors influencing the efficacy of soil microorganisms and explored ways to improve their effectiveness in sustainable soil fertility management. The importance of maintaining a diverse and healthy microbial community for sustainable agriculture and ecosystem management is emphasized throughout, particularly in addressing the unique challenges faced by African farmers. Potential applications of microbial-based approaches and microbe-centered best practices for soil fertility enhancement, specifically tailored to the needs of African farmers, are also explored. This chapter concludes by highlighting the need for further research and development of biofertilizers specifically adapted to climate change and other challenges of African agriculture. It advocates for policies and initiatives that promote the widespread adoption of biofertilizers, recognizing their potential to revolutionize sustainable farming practices and contribute to food security and environmental well-being across the continent.