Personalized cancer therapy is based on the precept that detailed molecular characterization of the patient's tumour and its microenvironment will enable tailored therapies to improve outcomes and decrease toxicity. The goal of personalized therapy is to target aberrations that drive tumour growth and survival, by administering the right drug combination for the right person. This is becoming increasingly achievable with advances in high-throughput technologies to characterize tumours and the expanding repertoire of molecularly targeted therapies. However, there are numerous challenges that need to be surpassed before delivering on the promise of personalized cancer therapy. These include tumour heterogeneity and molecular evolution, costs and potential morbidity of biopsies, lack of effective drugs against most genomic aberrations, technical limitations of molecular tests, and reimbursement and regulatory hurdles. Critically, the 'hype' surrounding personalized cancer therapy must be tempered with realistic expectations, which, today, encompass increased survival times for only a portion of patients.