In human and mouse up to 72% of all genomic loci show evidence of transcription from both sense and antisense strands. The benefit of the resulting natural antisense transcripts (NATs) remains unclear, largely because of a lack of significant correlation between gene ontology and antisense transcription. Here we suggest that a well defined group of NATs may be identified based on structural characteristics. Specifically, these NATs are processed transcripts that are complementary to the corresponding processed sense transcripts in exonic regions. Recent reports have established that co-expressed sense transcripts/NATs are processed into short RNAs. These so called endo-siRNAs are found in both sense and antisense orientation and were hypothesized to mediate pseudogene silencing. Here we propose that NATs are biologically important sources of endo-siRNAs. We also propose that endo-siRNAs are essential components of a regulatory network to control the mutagenic burden that unfolds on nucleic acid level without direct consequences on protein expression.