In solid tumors, neoplastic cells are surrounded by a specific microenvironment that integrates the extracellular matrix, lymphatic and blood vessels, and mesenchymal and immune cells, which together are known as the tumor microenvironment (TME). The TME governs many of the aggressive features of tumors, such as local invasion and metastasis. Additionally, new evidence indicates that the TME can trigger stem cell-like programs in cancer cells, forming cancer stem cells (CSC). Experimental and clinical studies suggest that CSCs are resistant to current common cancer therapies and are responsible for tumor recurrence. In this review, we will describe the TME by focusing on how matrix metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2) induce stemness and sustain stem cell maintenance. This reprogramming toward a CSC phenotype may be critical in tumor cell responses to chemotherapy and relapse with more aggressive tumor clones. Therefore, therapeutic agents targeting MMPs and COX-2 in the tumor microenvironment may become important drugs to control the establishment of CSCs and in the overall prognosis of the disease.