Cyanobacteria respond to environmental stress conditions by adjusting its photosynthesis machinery. When subjected to nutrient and high light stress, Synechococcus sp. PCC 7942 and other non-diazotrophic cyanobacteria degrade their phycobilisome, the light-harvesting complexes for photosynthesis. Phycobilisome degradation requires convergence of multiple signals onto the nblA gene. Despite considerable efforts to identify regulatory proteins involved in acclimation responses, the signal transduction mechanisms involved remain largely unknown. However, we show here that SipA, a protein that binds to the ATP-binding domain of the histidine kinase NblS, counteracts the function of the response regulator NblR in acclimation to stress, and is also involved in downregulation of the nblA gene. The integrity of the HLR1 element overlapping P(nblA-1) and P(nblA-2) promoters is required for downregulation of the nblA gene. Induction by NblR is strongly dependent on DNA sequences located at least 44 bp upstream transcription initiation from P(nblA-2), and is also hampered by point mutations at HLR1. Genetic evidence of the antagonistic roles of NblR and SipA at regulation of the nblA gene, chlorosis and survival from stress is presented.