Opposite to other immunoglobulin (Ig) classes and subclasses, there is no consensus on the definition of normal levels of serum total IgE. However, longitudinal studies on birth cohorts produced growth charts of total IgE levels in helminth-free and never atopic children and defining the normal ranges of total serum IgE concentration at the individual, rather than population, level. Accordingly, very ‘low IgE producers’ (i.e., children whose tIgE level belong to the lowest percentiles) became atopic while keeping their total IgE levels in a range considered ‘normal’ if compared to the general age-matched population but ‘abnormally high’ if projected on the tIgE growth chart against the trajectory of that child’s own percentile levels. In ‘low IgE producers’, the IgE-specific activity, i.e., the ratio between allergen-specific and total IgE, is more important than the absolute specific IgE levels to confirm causality between allergen exposure and allergic symptoms. Patients with allergic rhinitis or peanut anaphylaxis but low or undetectable allergen-specific IgE levels must therefore be reconsidered considering their total IgE levels. Low IgE producers have been also associated with common variable immunodeficiency, lung diseases, and malignancies. A few epidemiological studies have shown a higher risk of malignancies in very low IgE producers, leading to a debated hypothesis proposing a novel, evolutionistic-relevant function for IgE antibodies for antitumor immune surveillance.