Background and SignificanceThe application of heavy ion beams in cancer therapy must account for the increasing relative biological effectiveness (RBE) with increasing penetration depth when determining dose prescriptions and organ at risk (OAR) constraints in treatment planning. Because RBE depends in a complex manner on factors such as the ion type, energy, cell and tissue radiosensitivity, physical dose, biological endpoint, and position within and outside treatment fields, biophysical models reflecting these dependencies are required for the personalization and optimization of treatment plans.AimTo review and compare three mechanism‐inspired models which predict the complexities of particle RBE for various ion types, energies, linear energy transfer (LET) values and tissue radiation sensitivities.MethodsThe review of models and mechanisms focuses on the Local Effect Model (LEM), the Microdosimetric‐Kinetic (MK) model, and the Repair‐Misrepair‐Fixation (RMF) model in combination with the Monte Carlo Damage Simulation (MCDS). These models relate the induction of potentially lethal double strand breaks (DSBs) to the subsequent interactions and biological processing of DSB into more lethal forms of damage. A key element to explain the increased biological effectiveness of high LET ions compared to MV x rays is the characterization of the number and local complexity (clustering) of the initial DSB produced within a cell. For high LET ions, the spatial density of DSB induction along an ion's trajectory is much greater than along the path of a low LET electron, such as the secondary electrons produced by the megavoltage (MV) x rays used in conventional radiation therapy. The main aspects of the three models are introduced and the conceptual similarities and differences are critiqued and highlighted. Model predictions are compared in terms of the RBE for DSB induction and for reproductive cell survival.Results and ConclusionsComparisons of the RBE for DSB induction and for cell survival are presented for proton (1H), helium (4He), and carbon (12C) ions for the therapeutically most relevant range of ion beam energies. The reviewed models embody mechanisms of action acting over the spatial scales underlying the biological processing of potentially lethal DSB into more lethal forms of damage. Differences among the number and types of input parameters, relevant biological targets, and the computational approaches among the LEM, MK and RMF models are summarized and critiqued. Potential experiments to test some of the seemingly contradictory aspects of the models are discussed.