PKC is a ubiquitously expressed serine/threonine protein kinase, sit at the junction of many signaling pathway and play key roles in mediating myriad cellular functions. Therefore, the precise control of PKC directed signal transduction is essential for cellular homeostasis. Deregulation of PKC-mediated signaling leads to the several pathophysiological conditions including cancer. The activity of PKC is regulated by multiple molecular mechanisms such as phosphorylation, co-factor recruitment, interaction with binding partner proteins and cellular localization. Moreover, number of natural and synthetic compounds available that are involves in controlling the PKC mediated signal transduction, but a drug that can specifically regulate the activity of particular isoform of the PKC is not known. Therefore, it is essential to gain an insight into how the PKC activated and presumed to work. This review will provide comprehensive idea about regulation of PKC at various activation steps, a short account of some of available efforts in cellular transformation, challenges, and possibilities to design novel PKC modulators.