Background: Immunoglobulin G (IgG) subclass deficiencies and isolated IgA, IgM, IgE deficiencies have all been described in the literature with variable prevalence. Methods: These isotype deficiencies have a variable presentation from asymptomatic to recurrent infections resistant to prophylactic antibiotics. Results: Atopic disorders and autoimmune diseases are common comorbidities. IgE deficiency has been associated with impaired vaccine response and an increased risk of malignancy, particularly in patients with no allergic comorbidities and those with non-common variable immunodeficiency (CVID) humoral immunodeficiency, IgM deficiency, IgG2 deficiency, and CD4 lymphopenia. Conclusion: Close monitoring for malignancy should be strongly considered for these patients who are at risk. Treatment is variable and may include antimicrobial therapies for illnesses and prophylactic antibiotics in select patients, and immunoglobulin replacement can be considered for patients with refractory, recurrent infections.