Antigenic variation and immune evasion by Plasmodium falciparum parasitized erythrocytes are mediated by expression switches among members of the multicopy var gene family. Here we describe a cluster of var genes on chromosome 12 that showed spontaneous recombination and switches in the transcription of individual genes. The transcription switches were not associated with sequence changes in promoter regions. Transfected episomes containing a luciferase reporter under control of a var promoter were expressed regardless of the transcriptional status of the endogenous promoter. The results suggest epigenetic regulation of P. falciparum var gene transcription that depends upon the local structure of chromatin and its associated proteins.