Lipids and membranes are often strongly altered in various diseases and pathologies, but are not often targeted for therapeutic advantage. In particular, the sphingolipids are particularly sensitive to altered physiology and have been implicated as important players in not only several rare hereditary diseases, but also other major pathologies, including cancer. This review discusses some potential targets in the sphingolipid pathway and describes how the initial drug compounds have been evolved to create potentially improved therapeutics. This reveals how lipids and their interactions with proteins can be used for therapeutic advantage. We also discuss the possibility that modification of the physical properties of membranes could also affect intracellular signaling and be of therapeutic interest.