Concurrent treatment with radiotherapy and chemotherapy has emerged as an effective strategy to improve clinical outcome of cancer. In addition to combining radiation with classical anticancer agents, several new biological response modifiers are under investigation in pre-clinical and clinical studies. Synthetic alkylphospholipids are anticancer agents that in contrast to most anticancer drugs, do not target DNA, but insert in the plasma membrane and subsequently induce a broad range of biological effects, ultimately leading to cell death. Alkylphospholipids kill tumor cells directly by induction of both apoptotic and non-apoptotic cell death, and indirectly by interference with critical signal transduction pathways involved in phospholipid metabolism and survival. Due to their distinct mode of action, these drugs are considered as attractive candidates to combine with radiotherapy. In this review, we will discuss several alkylphospholipids that reached clinical application. These include first-generation alkyl-lysophospholipids edelfosine and ilmofosine, second-generation alkylphosphocholine-prototype miltefosine and more recently developed analogues perifosine and erucylphosphocholine. We focus on mechanisms of action and the rationale to combine these agents with radiotherapy. The preclinical results on molecular targeting underlying this approach will be reviewed, concluded with first clinical data on combined treatment of radiotherapy with perifosine.