Insertions and deletions (collectively indels) obviously have a major impact on genome evolution. However, before large-scale data on indel polymorphism became available, it was difficult to estimate the strength of selection acting on indel mutations. Here, we analyze indel polymorphism and divergence in different compartments of the Drosophila melanogaster genome: exons, introns of different lengths, and intergenic regions. Data on low-frequency polymorphisms indicate that 0.036–0.039 short (1–30 nt) insertion mutations and 0.085–0.092 short deletion mutations, with mean lengths 3.23 and 4.78, respectively, occur per single-nucleotide substitution. The excess of short deletion over short insertion mutations implies that indel mutations of these lengths should lead to a loss of approximately 0.30 nt per single-nucleotide replacement. However, polymorphism and divergence data show that this deletion bias is almost completely compensated by selection: Negative selection is stronger against deletions, whereas insertions are more likely to be favored by positive selection. Among the inframe low-frequency polymorphic mutations in exons, long introns, and intergenic regions, selection prevents a larger fraction of deletions (80–87%, depending on the type of the compartment) than of insertions (70–82%) or single-nucleotide substitutions (49–73%), from reaching high frequencies. The corresponding fractions were the lowest in short introns: 66%, 47%, and 15%, respectively, consistent with the weakest selective constraint in them. The McDonald–Kreitman test shows that 32–46% of the deletions and 60–73% of the insertions that were fixed in the recent evolution of D. melanogaster are adaptive, whereas this fraction is only 0–29% for single-nucleotide substitutions. [ABSTRACT FROM AUTHOR]