AbstractNucleotide second messengers are highly versatile signaling molecules that regulate a variety of key biological processes in bacteria. The best‐studied examples are cyclic AMP (cAMP) and bis‐(3′–5′)‐cyclic dimeric guanosine monophosphate (c‐di‐GMP), which both act as global regulators. Global regulatory frameworks of c‐di‐GMP and cAMP in bacteria show several parallels but also significant variances. In this review, we illustrate the global regulatory models of the two nucleotide second messengers, compare the different regulatory frameworks between c‐di‐GMP and cAMP, and discuss the mechanisms and physiological significance of cross‐regulation between c‐di‐GMP and cAMP. c‐di‐GMP responds to numerous signals dependent on a great number of metabolic enzymes, and it regulates various signal transduction pathways through its huge number of effectors with varying activities. In contrast, due to the limited quantity, the cAMP metabolic enzymes and its major effector are regulated at different levels by diverse signals. cAMP performs its global regulatory function primarily by controlling the transcription of a large number of genes via cAMP receptor protein (CRP) in most bacteria. This review can help us understand how bacteria use the two typical nucleotide second messengers to effectively coordinate and integrate various physiological processes, providing theoretical guidelines for future research.