Cow’s milk allergy (CMA) affects 2–3% of infants. It resolves in the great majority spontaneously during childhood. CMA encompasses a spectrum of clinical and immunologic characteristics. Non-IgE-mediated allergy typically resolves earlier than IgE-mediated allergy. The most documented prognostic characteristic is that intense-specific IgE response predicts persistence of CMA. Low serum levels of cow’s milk (CM)-specific IgG4 are also associated with persistent CMA. Natural development of tolerance involves an immunologic shift where Th2 responses diminish, and Th1 as well as T regulatory cell responses strengthen. Accordingly, specific IgE levels decrease and specific IgG4, possibly also IgA, levels increase in serum. Specific oral immunotherapy (OIT) with CM induces desensitization in most cases where spontaneous recovery has not yet occurred. Data on long-term tolerance induction are still scarce. According to current research data, the immunologic changes induced by OIT resemble those seen during natural development of tolerance.