“Psychological stress” occurs when an individual perceives that environmental demands tax or exceed his or her adaptive capacity. According to the Cochrane Database of Systematic Reviews, the best validated approach covering both stress management and stress treatment is the Cognitive Behavioral (CBT) approach. CBT has undergone a very large number of trials in research contexts. However, it has been less efficacious in clinical contexts and it has become obvious that CBT has some failings when applied in general practice. INTERSTRESS is a EU-funded project that aims to design, develop and test an advanced ICT-based solution for the assessment and treatment of psychological stress that is able to address three critical limitations of CBT: a) the therapist is less relevant than the specific protocol used. b) the protocol is not customized to the specific characteristics of the patient; c) the focus of the therapy is more on the top-down model of change (from cognitions to emotions) than on the bottom-up (from emotions to cognitions). To reach this goal the INTERSTRESS project applies an innovative paradigm for e-health – Interreality – that integrates assessment and treatment within a hybrid environment, bridging physical and virtual worlds. On one side, the patient is continuously assessed in the virtual and real worlds by tracking the behavioral and emotional status in the context of challenging tasks (customization of the therapy according to the characteristics of the patient). On the other side, feedback is continuously provided to improve both the appraisal and the coping skills of the patient through a conditioned association between effective performance state and task execution behaviors (improvement of self efficacy). Within this conceptual framework, it is possible to set up and test psychological treatments that could be extended also beyond the traditional research and clinical setting by using more and more emerging mobile technology to deliver real-time interventions during daily activities and ecological contexts.