Cyanobacteria represent the largest and most diverse group of prokaryotes capable of performing oxygenic photosynthesis and are frequently found in environments contaminated with heavy metals. Several studies have been performed in these organisms in order to better understand the effects of metals such as Zn, Cd, Cu, Ni and Co. In Synechocystis sp. PCC 6803, genes involved in Ni, Co, Cu and Zn resistance have been reported. However, proteomic studies for the identification of proteins modulated by heavy metals have not been carried out. In the present work, we have analyzed the proteomic pattern alterations of the cyanobacterium Synechocystis sp. PCC 6803 in response to Ni, Co and Cd in order to identify the metabolic processes affected by these metals. We show that some proteins are commonly regulated in response to the different metal ions, including ribulose1,5-bisphosphate carboxylase and the periplasmic iron-binding protein FutA2, while others, such as chaperones, were specifically induced by each metal. We also show that the main processes affected by the metals are carbon metabolism and photosynthesis, since heavy metals affect proteins required for the correct functioning of these activities.This is the first report on the proteomic profile of Synechocystis sp. PCC 6803 wild type and mutant strains for the identification of proteins affected by the heavy metals Ni, Co and Cd. We have identified proteins commonly responsive to all three metals and also chaperones specifically modulated by each metal. Our data also supports previous studies that suggest the existence of additional sensor systems for Co.