Uncertainty is involved in each and every step of the diagnostic process. Trying to eliminate doubt altogether is too costly, is likely to fail, and may lead to patient harm. Acknowledging this, the threshold approach aims to optimize diagnosis-making by adopting the explicit use of probability estimates and by discouraging the pursuit of 100% certainty. Yet physicians are affected by cognitive biases which compromise their probabilistic reasoning and may lead to unreliable estimates. Health informatics tools helping to overcome human limitations by empowering physicians to handle probabilities are needed to increase the efficiency of diagnostic process.