Solid tumors grow within a complex microenvironment composed of diverse cell types such as fibroblasts, endothelial cells, mast cells, macrophages and immune cells that are attracted by tumor cell derived factors and embedded in an extracellular matrix. Molecular and cellular interactions between epithelial cells and cells surrounding the tumor stroma promote growth, invasion and spread of tumors. To delay or impede tumor growth, the tumor microenvironment (TME) is increasingly being explored as a potential therapeutic target for which novel strategies are developed. </p><p> This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed.