Environmental pressures can direct genomes from a normal to a more or less pronounced imbalance in the base composition. These pressures seem to occur relatively often since genomes with a deviation from a normal base composition are widespread throughout lower eukaryotes. These genomes show altered codon usage and enrichment for the preferred bases in intron and intergenic regions. Techniques designed for large scale sequencing and assembly of genomes with normal base composition will fail with these unusual genomes. Additionally, the currently available analysis tools are mainly suitable for gene finding in genomes with normal base composition. In recent years some large scale genome analysis projects involving species with a skew directed to a very high AT content were initiated. These projects are encountered with sequencing, assembly, and gap closure problems due to the high AT content. These problems can only be overcome with additional techniques, which partly were developed and used in the on going projects. In this review some characteristic aspects of AT rich genomes, the progress of the Dictyostelium discoideum and the Plasmodium falciparum projects, as well as techniques specifically used for the sequencing of these genomes are highlighted.