In the past decades, cancer medicine studies have mainly focused on tumor cell biology as the main promoter of solid tumor progression. However, tumor biology does not explain the intertwinement and ambiguity of the tumors' territory. Recently, the approach of understanding cancer has shifted from investigating the biology of tumor cells to studying the microenvironment surrounding them. MicroRNAs (miRNAs), which play a role in exploiting indigenous stromal cells and are components that cooperate and produce a favorable microenvironment for progressive tumor formation, have been implicated in numerous processes essential for tumor initiation and growth. Understanding the mechanisms underlying interactions between tumor cells and their adjacent environment holds many promises for the future of cancer-targeted therapies. Herein, we provide a step-by-step account of miRNA involvement in tumor–microenvironment interactions as the micromediators of tumor cell and stroma communications. We also focus on the clinical challenges in using miRNAs tof overcome therapy resistance mechanisms and tumor heterogeneity bias in cancer therapy. © 2015 Wiley Periodicals, Inc.