Traditionally, the studies on cancer growth and progression have been focused on the transformed, malignant cells. However, it is now well recognized that the tumour stroma represents a crucial parameter in tumour development, growth and progression. Indeed, several cancers are characterized by a prominent stromal compartment and it is the interactions between cancer cells, stromal cells and extracellular matrix (ECM) components that control the overall tumour growth. Among stromal cells, fibroblasts represent the most important type. They are responsible for deposition and remodeling of ECM components, as well as for the release of cytokines and growth factors, including platelet-derived growth factor (PDGF), acting in a paracrine manner on cancer cells. In this review we elucidate the role of tumor stroma interactions, the roles of PDGF receptor signaling in cancer-associated fibroblasts via alteration of stromal matrix composition and the mitogenic effects of cancer-derived PDGFs. Focus on the targeting of tumor microenvironment at the level of PDGF/PDGF receptor (PDGFR) is also presented as to stimulate further studies for designing and development of novel pharmaceutical agents and combined pharmaceutical interventions. Conclusively, PDGF/PDGFR axis is of paramount importance in the tumour microenvironment context and the inhibition of PDGF receptors’ activation represents a major target for future anticancer therapies.