Conventional chemotherapy-based drug combinations have, until recently, been the backbone of most therapeutic strategies for cancer. In a time of emerging rationale drug development, targeted therapies are beginning to be added to traditional chemotherapeutics to synergistically enhance clinical responses. Of note, the importance of pro-apoptotic ceramide in mediating the anti-cancer effects of these therapies is becoming more apparent. Furthermore, reduced cellular ceramide in favour of pro-survival sphingolipids correlates with tumorigenesis and most importantly, drug resistance. Thus, agents that manipulate sphingolipid metabolism have been explored as potential anti-cancer agents and have recently demonstrated exciting potential to augment the efficacy of anti-cancer therapeutics. This review examines the biology underpinning these observations and the potential use of sphingolipid manipulating agents in the context of existing and emerging therapies for haematological malignancies.