Ecthyma contagiosum (orf), a worldwide cause of the hand pustule, is caused by orf virus, a member of the genus Parapoxvirus, which causes an epitheliotropic zoonotic infection that spreads from ruminants (even-toed ungulate mammals such as sheep or goats) to humans. Similar members within the poxvirus family can cause a clinically identical viral pustule, which is spread to humans from the respective animal host reservoirs. These entities are impossible to clinically differentiate in the absence of social history or specific polymerase chain reaction studies, though their frequency does vary based on location across the globe.Although its 1-cm solitary hand pustule often is easily diagnosed by the experienced dermatologist, the goal of this review is to expand the understanding of the presentation, differential diagnosis, and treatment of this condition. We present 5 clinical cases of orf. Special care also has been taken to expand on our report of the unique associated cultural and social elements that the expert diagnostician should obtain to determine etiology.Early and rapid diagnosis of this classic condition are critical to prevent unnecessary biopsies or extensive testing, and determination of etiology can be important to prevent reinfection or spread to other humans by the same infected animal.