Outbreaks of buffalopox or pox-like infections affecting buffaloes, cows and humans have been recorded in many parts of the world. Since the first outbreak in India, a large number of epidemics have occurred. Unlike in the previous years, generalized forms of the disease are now rare; however, there are severe local forms of the disease affecting the udder and teats, leading to mastitis thereby undermining the productivity of milk animals. The causative agent buffalopox virus (BPXV) is a member of the Orthopoxvirus, and is closely related to Vaccinia virus (VACV), the type-species of the genus. Earlier studies with restriction fragment length polymorphism and recent investigations involving sequencing of the genes that are essential in viral pathogenesis have shown that BPXV is phylogenetically very closely related to VACV and may be considered as a clade of the latter. The review discusses the epidemiology, novel diagnostic methods for the disease, and molecular biology of the virus, and infers genetic relationships of BPXV with other members of the genus.