African trypanosomes are protozoan parasites that reside in the mammalian bloodstream where they constantly confront the immune responses directed against them. They keep one-step-ahead of the immune system by continually switching from the expression of one variant surface glycoprotein (VSG) on their surface to the expression of another immunologically distinct VSG-a phenomenon called antigenic variation. About 1000 VSG genes (VSGs) and pseudo-VSGs are scattered throughout the trypanosome genome, all of which are transcriptionally silent except for one. Usually, the active VSG has been recently duplicated and translocated to one of about 20 potential bloodstream VSG expression sites (B-ESs). Each of the 20 potential B-ESs is adjacent to a chromosomal telomere, but only one B-ES is actively transcribed in a given organism. Recent evidence suggests the active B-ES is situated in an extra-nucleolar body of the nucleus where it is transcribed by RNA polymerase I. Members of another group of about 20 telomere-linked VSG expression sites (the M-ESs) are expressed only during the metacyclic stage of the parasite in its tsetse fly vector. Progress in sequencing the African trypanosome genome has led to additional insights on the organization of genes within both groups of ESs that may ultimately suggest better ways to control or eliminate this deadly pathogen.