Clinical manifestations of disease depend upon host's immune response that is induced by pathogen and modified by the host's innate and adaptive immunity. Immunocompetent children of similar age and nutrition evoke different responses to the same pathogen varying from benign to potentially fatal condition. This results in diverse clinical presentations of a disease, that is different from the standard expected pattern and thus, poses a diagnostic challenge. Even, subsequent progression of a disease is also variable. It is the balance between immune stimulation, immune suppression and immune tolerance that decides the outcome. In case of balanced response, child recovers completely without any damage. However at times, cure is at the expense of permanent sequalae while in case of unfavourable immune response, survival may not be certain inspite of successful therapy. Symptoms and physical signs of primary disease often overlap with those caused by host's immune response. In such a situation, it is difficult to decide whether therapy of primary disease has failed due to drug resistance or whether persistence or deterioration is the result of immune response. Occasionally pathogen can transform into "superantigen" that may lead to "cytokine storm". Resulting immune-mediated complications may endanger life and at best, treated symptomatically. Immune suppressive drugs such as steroids, chemotherapeutic agents, IVIG or specific antibodies may not be able to suppress undesirable immune response. It is not just the immune suppression that is required but ideally immune modulation. Immune modulation refers to enhancing protective responses while avoiding destructive ones. At present, science falls short of anticipating harmful immune responses and lacks specific immune intervention.Laboratory test results are also dependent on host response and hence need cautious interpretation based on clinical profile in consideration with multiple variables. In final analysis, fight between host and pathogen is a complex one and often unpredictable. It is hoped that most children evoke favourable response but pediatrician has to be watchful even in the most benign disease.