Protein kinase C is a family of ubiquitously expressed signal transducing proteins. The hallmark for PKC activation is its translocation to membranes following generation of lipid second messengers. This process is mediated by C1 and C2 membrane-targeting modules, whose engagement on membranes provides energy for a conformational change crucial to PKC activity. Novel and conventional subfamilies of PKC have two C1 domains, namely C1A and C1B, each of which contain a binding pocket for a messenger. Several studies addressed the issue of simultaneous activation of both C1 domains by specifically designed bivalent activators based on phorbol esters, benzolactam and other PKC ligands. Many bivalent ligands displayed 1-2 orders of magnitude higher potency then their monovalent congeners. Most effective were the “dimeric” ligands linked with 10-14 carbon spacers. Lower than predicted potency and lack of marked isoform selectivity indicate that those compounds do not activate both C1 domains at the same time, or that process is unfavored due to steric or conformational reasons. However, high binding affinity for some of them provides hope that related PKC activators that are isoform selective can be developed. As to the nature of the linkers: flexible and lipophilic oligomethylene chains proved superior over flexible and hydrophilic oligoethylene glycol or rigid and lipophilic benzene in recruiting PKC to the membranes.