Cyanobacteria are considered as the first autotroph organisms which are present in almost all possible environments. However, abiotic stresses like temperature, heavy metals, and salt influence the normal metabolic functions and adversely affect its photosynthetic apparatus by increasing reactive oxygen species. Cyanobacteria have evolved themselves in order to respond against harsh conditions, in the form of either change in membrane structure, response of stress-responsive genes, regulatory pathways, or regulating secondary metabolite secretion. Such physiological responses lead to adaptation and acclimatization toward changing environments and provide survival advantage to these ancient organisms. Moreover, the presence of various bioactive compounds like phenolics, flavonoids, alkaloids, phytoprotective metabolites, phytohormones, and mycosporine like amino acids favors cyanobacterial defense strategy, of which the majority is present in plant system too. The purpose of this chapter is to deliver recent knowledge regarding the adaptive response of cyanobacteria including molecular chaperons and two-component system protein. Effects of abiotic stress in membrane structure and defense strategy along with the role of bioactive compounds are also included. © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023.