Dobzhansky, who was born in Nemirov, in Ukraine, graduated in zoology from Kiev University in 1921; he remained there to teach zoology before moving to Leningrad, where he taught genetics. In 1927 he took up a fellowship at Columbia University, New York, where he worked with T. H. Morgan. Morgan was impressed by Dobzhansky's ability and, when the fellowship was completed, offered him a teaching post at the California Institute of Technology. Dobzhansky accepted and became an American citizen in 1937.

Dobzhansky studied the fruit fly (Drosophila) and demonstrated that the genetic variability within populations was far greater than had been imagined. The high frequency of potentially deleterious genes had previously been overlooked because their effects are masked by corresponding dominant genes. Dobzhansky found that such debilitating genes actually conferred an advantage to the organism when present with the normal type of gene, and therefore they tended to be maintained at a high level in the population. Populations with a high genetic load – i.e. many concealed lethal genes – proved to be more versatile in changing environments. This work profoundly influenced the theories on the mathematics of evolution and natural selection with regard to Mendelism.

In addition, Dobzhansky wrote many influential books, including Genetics and the Origin of Species (1937), a milestone in evolutionary genetics.