Arginine is a conditionally essential amino acid that has been identified as an important player in a number of biologic processes, including normal functions of the cardiovascular and immune systems. Numerous studies have demonstrated that arginine is necessary for cellular growth and can become limiting in states of rapid growth like malignancy. Given this requirement for arginine in malignant cells, investigators have examined the potential for arginine deprivation therapy as an adjuvant treatment for cancers that are unable to synthesize arginine de novo. Additionally, arginine has been identified as being critically important for immune surveillance that targets and destroys malignant cells. Thus, paradoxically, arginine has been identified as being both necessary for cancer growth and normal immune destruction of malignant cells. A number of factors, including the type of cancer, expression of arginine synthetic genes, tumor microenvironment and host immune cell-cancer cell interactions, can affect the progression of malignancy. Herein we review the data supporting arginine deprivation and supplementation in cancer therapies and the currently registered trials that aim at understanding which of these strategies may lead to advances in cancer therapy.