Many bacteria are naturally competent, able to actively transport environmental DNA fragments across their cell envelope and into their cytoplasm. Because incoming DNA fragments can recombine with and replace homologous segments of the chromosome, competence provides cells with a potent mechanism of horizontal gene transfer as well as access to the nutrients in extracellular DNA. This review starts with an introductory overview of competence and continues with a detailed consideration of the DNA uptake specificity of competent proteobacteria in the Pasteurellaceae and Neisseriaceae. Species in these distantly related families exhibit strong preferences for genomic DNA from close relatives, a self-specificity arising from the combined effects of biases in the uptake machinery and genomic overrepresentation of the sequences this machinery prefers. Other competent species tested lack obvious uptake bias or uptake sequences, suggesting that strong convergent evolutionary forces have acted on these two families. Recent results show that uptake sequences have multiple "dialects," with clades within each family preferring distinct sequence variants and having corresponding variants enriched in their genomes. Although the genomic consensus uptake sequences are 12 and 29 to 34 bp, uptake assays have found that only central cores of 3 to 4 bp, conserved across dialects, are crucial for uptake. The other bases, which differ between dialects, make weaker individual contributions but have important cooperative interactions. Together, these results make predictions about the mechanism of DNA uptake across the outer membrane, supporting a model for the evolutionary accumulation and stability of uptake sequences and suggesting that uptake biases may be more widespread than currently thought. N aturally competent bacteria actively pull DNA fragments from their environment into their cells. These fragments provide nucleotides, but high similarity with the chromosome also allows them to change the cell's genotype by homologous recombination, a process called natural transformation ( Fig. 1; reviewed in references 1, 2, 3, 4, and 5). Most competent bacteria that have been tested can take up DNA from any source, but species in two distantly related families of Gram-negative bacteria, the Pasteurellaceae and the Neisseriaceae, show strong preferences for DNAs containing short sequences that are highly overrepresented in their own genomes, leading to preferential uptake of conspecific DNA (6). This self-specificity both raises questions about and provides a tool for investigating the evolution of competence and the mechanism of DNA uptake.We begin with a general overview of competence, emphasizing the evolutionary issues. We then describe the two components that together create self-specificity, sequence biases in the DNA uptake machinery and overrepresentation of uptake sequences in the genomes, highlighting recent work on the mechanism and evolution of uptake biases in the two families and an evolutionary model that accounts for upt...