<p>Bone marrow mesenchymal stromal cells (BMSCs) are multipotent progenitors that can differentiate into osteoblasts or adipocytes. A dynamic equilibrium exists between osteogenesis and adipogenesis, referred to as the bone–fat balance. Under pathological conditions, BMSCs often display reduced osteogenic potential and enhanced adipogenic differentiation, resulting in a disrupted bone–fat balance that contributes to the development and progression of bone disorders such as Osteoporosis. Understanding the factors that bidirectionally regulate this balance is essential for identifying novel therapeutic targets for Osteoporosis. This review summarizes the regulatory mechanisms that can modulate osteogenic and adipogenic differentiation in both directions. The identified regulators are systematically categorized into four main groups according to their molecular characteristics: proteins, chemical compounds, non-coding RNAs (ncRNAs), and physical factors. Each regulatory factor employs distinct molecular strategies to influence the balance between bone and fat. This framework provides an integrated understanding of BMSCs fate determination and highlights possible therapeutic approaches targeting the bidirectional regulators of osteogenic and adipogenic differentiation.</p>