Genetic analysis of orthopoxviruses has contributed substantially to our understanding of the functional organization of the poxvirus genome, and individual mutants provide invaluable tools for future studies of poxvirus biology. Deletion and transposition mutants, localized primarily in the termini of the genome, may be particularly useful for studying virus host range and pathogenicity. Numerous drug resistant and dependent mutants provide keys to understanding a wide variety of virus genes. A large number of well-characterized ts mutants, clustered in the center of the virus genome, are taking on an increasingly important role in research on the function of essential poxvirus genes. Genetic characterization of orthopoxviruses has progressed rapidly during the past decade, and one can reasonably anticipate a time when mutants will be available for the study of any poxvirus gene. Considerable progress toward this goal can be achieved through organized attempts to integrate and further characterize existing mutant collections and through the continued isolation and characterization of deletion, drug resistant, and ts mutants using established techniques. The most exciting possibility is that soon techniques will be available for directed mutagenesis to conditional lethality of any essential poxvirus gene.