Nitric oxide (NO) exerts physiopathological effects based mainly on its concentration. Thus, it facilitates or inhibits cancer-promoting characteristics. This review discusses the role of NO and its network of partners in tumor progression and angiogenesis: prostaglandin E 2 (PGE-2) and its producing enzymes, cyclooxigenase 2 (COX-2) and microsomal PGE synthase 1 (mPGES-1), and epidermal growth factor receptor (EGFR) signaling. Understanding the molecular mechanisms and cross-talk modulating NO effects by PGE-2 and EGFR and vice versa allows us to develop better therapeutic strategies for cancer treatment.