Hypoxia-activated prodrugs (HAPs) present a conceptually elegant approach to not only overcome, but better yet, exploit intra-tumoural hypoxia. Despite being successfulin vitroandin vivo, HAPs are yet to achieve successful results in clinical settings. It has been hypothesised that this lack of clinical success can, in part, be explained by the insufficiently stringent clinical screening selection of determining which tumours are suitable for HAP treatments. Taking a mathematical modelling approach, we investigate how tumour properties and HAP-radiation scheduling influence treatment outcomes in simulated tumours. The following key results are demonstratedin silico:(i)HAP and ionising radiation (IR) monotherapies may attack tumours in dissimilar, and complementary, ways.(ii)HAP-IR scheduling may impact treatment efficacy.(iii)HAPs may function as IR treatment intensifiers.(iv)The spatio-temporal intra-tumoural oxygen landscape may impact HAP efficacy. Ourin silicoframework is based on an on-lattice, hybrid, multiscale cellular automaton spanning three spatial dimensions. The mathematical model for tumour spheroid growth is parameterised by multicellular tumour spheroid (MCTS) data.