The medicinal powers of opium poppy-derived extracts now called ‘opioids’ and the importance of vasculature in maintaining life were realized by ancient civilizations. However, the association of the two with each other has emerged in the last decade. Opioid receptors, including the mu opioid receptor (MOR) which mediates opioid analgesia, are present on the endothelium. Analgesic opioids such as morphine and its congeners stimulate growth- and survival promoting signaling directly via MOR and also by co-activating receptor tyrosine kinases for vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, etc. in the endothelial cells. Opioid signaling translates into increased tumor angiogenesis, tumor growth, metastases and reduced survival in mice. Additionally, opioids modulate the tumor microenvironment by acting on diverse cellular milieu of the tumor. Increased density of MOR in human tumors as compared to normal tissue, suggests a role for MOR in cancer. Based on experimental studies and MOR expression on human tumors it is critical to examine the role of opioids in cancer progression and survival in patients treated with opioids for severe pain.