Transmembrane receptors are usually seen as on and off switches: when the specific ligand is bound, the receptor is on and transduces a downstream signal, whereas when the ligand is absent, the receptor is off. Over the last two decades several reports have argued for an alternative view where some receptors, depending on the context, will be active both in the presence and in the absence of ligand, being sort of onA and onB switch rather than on and off. These receptors have been named dependence receptors (DR) and they share the ability to actively trigger cell death when unbound by their respective ligands. DRs have been shown to be important guardians of tissue homeostasis. In pathological settings such as cancer, DRs are seen as tumour suppressors and a clinical trial is ongoing to assay whether these DRs can be used to provide clinical benefit by triggering cancer cell death. In this review we are reviewing this functional family of receptors and underlying their promising potential for targeted therapy against cancer.