Natural antisense transcripts (NATs) are noncoding, processed RNAs that originate from the opposite strand of protein-coding genes. They can be considered as long noncoding RNAs (lncRNAs) that originate from the same genomic locus as their potential regulatory target and are therefore particularly versatile regulators of gene expression. Their potential to form structures such as hairpins, R-loops, triple helices, and RNA-RNA hybrids with the related sense transcript provides a myriad of opportunities to modulate the processing of their cognate protein-coding transcript and to bind to chromatin-modifying enzymes and transcription factors that eventually shape the activity of affected genes. Moreover, the close proximity of the effector (NAT) and its target (the related protein-coding sense gene) minimizes off-target effects and enables condensate formation to regulate sense transcription. The fact that NATs are generally processed and modified with mRNA-like features expands their regulatory reach to the cytoplasm, where examples of NATs regulating mRNA stability and translation efficiency have been reported. Considering their versatility, it comes as no surprise that an ever-increasing number of NATs are associated with development and disease. Conversely, bidirectional transcription can have detrimental effects on adjacent genes. For example, double-stranded RNA (dsRNA) is highly immunogenic or, as in Caenorhabditis elegans, may lead to transgenerational gene silencing. These challenges may constitute evolutionary pressure to develop mitigating strategies.