Vesiculobullous diseases are heterogeneous mucocutaneous disease entities of varying etiologies, ranging from infections to autoimmune disorders to manifestations of underlying chronic health conditions. Since all etiologies are associated with vesicular or bullous lesions, diagnosing these conditions can be challenging. However, a thorough history and considering a patient’s comorbidities can narrow the differential diagnosis and point to a particular etiology in many cases. A biopsy of active lesions with microscopic analysis can clarify the diagnosis in less obvious cases. This article explores the most common vesiculobullous diseases primary care clinicians should consider when evaluating and treating patients.