Cardiovascular diseases are life-threatening conditions which can develop through the misregulation of complex cellular signaling networks. Several surveillance mechanisms have evolved to discriminate self from foreign nucleic acids and accordingly trigger effective cellular responses to target the pathogenic threats. Several efforts have been made to understand the role of pattern recognition receptors (PRRs) and nucleic acids in this condition. Understanding these molecular interactions is not only important for exploring the molecular mechanisms underlying cardiac pathophysiology, but also in the development of novel therapeutics. The application of interdisciplinary approaches that integrate high-throughput genomics, proteomics, biostatistics, and computational biology will open avenues to novel multi-hit therapeutic approaches for cardiac diseases. Here, we describe the current knowledge in nucleic acids research in relation to their discrimination, immune activation, and signaling pathways and their potential to cause cardiac pathophysiology.