Malignant cells result from the accumulation of genetic alterations that impinge into the components of signal transduction pathways controlling cell growth, differentiation and apoptosis. One of the critical pathways is related to the regulation of the phospholipid homeostasis. The identification of the molecular components involved in normal cell growth regulation altered upon transformation is required for the development of chemotherapeutic interventions against transformed cells. Discovery of new chemotherapeutic agents is one of the most promising ways to improve our success against cancer, and rational drug design is a key factor to achieve this goal. Evidence supporting choline kinase and phospholipase D as such novel targets is provided.