Salt stress involves a complex network of factors affecting various metabolic processes in cyanobacteria. The discovery and identification of genes responsible for salt tolerance and clarifying their network have enhanced our understanding of stress tolerance and resilience in photosynthetic organisms. In addition to classical genetic approaches for the discovery of salt-response genes in salt-tolerant species, complete genome sequence analysis and comparative genomic analysis are potentially useful approaches for the discovery of stress-related genes. It is now feasible to study environmental adaptation based on genome information. The advantages conferred by high-throughput methods together with bioinformatic tools have facilitated the identification of stress-associated gene families across species based on homology and co-occurrence gene families. Here, we demonstrate that cyanobacterial genomes can provide resources and evidence about the nature of the defense mechanisms underlying halotolerance, including what constitutes the genetic basis for these mechanisms. Cyanobacteria that thrive in saline environments acquired adaptive mechanisms, proceeded genome evolution, evolved acidic proteomes, and effectively supplied molecular machineries for halotolerance, leading to their success in stressful environments. Genomic technologies have thus provided the capacity to unlock the complex interactions between microorganisms and entire biological systems. Genomic and omics-based data is increasingly used in research studies.