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Background : Our insight into the neurobiological dynamics underlying the processes that may over time cumulate into syndromes like burn-out and depression is rapidly developing. A recent, though important, step has been to combine the relevant parameters of multiple domains (physiological, endocrine, social/emotional) to optimize prognostic accuracy. This is of relevance as initially subtle neurobiological disturbances associated with stress may indicate the start of a negative and potentially dangerous trend, both for physical and psychological health. Methods : On the basis of the regular monitoring of key variables of allostatic processes (like heart rate variability, corticosteroid concentrations, and psychosocial status), risks scores for internalizing development can be calculated. When repeatedly collected by means of a standardized assessment protocol, it becomes possible to conduct trend analyses, which may potentially indicate development towards aversive outcomes like burn-out (in labour environments) or for example depression. Results : On the basis of available data, algorithms have been developed combining diverse allostatic key variables into multi-level prognostic models (low–medium–high risk for internalizing development). On the basis of these models, a standardized assessment protocol is developed using state-of-the-art information technology to make the application as consumer friendly as possible. Conclusions : Although some technical developments are necessary to optimize the potency of assessment protocols like the present one (e.g., sensor technology able to measure or estimate corticosteroid concentrations “on the spot”), the used algorithms do not only seem to provide valid prognostic information, though essential indicators for easy to apply preventive strategies as well. These could be instrumental in averting long-term negative psychological outcomes.