The atypical protein kinase C (PKC) isoforms (aPKC) have been implicated in the regulation of a number of essential signaling events. Early studies using dominant-negative mutants suggested that they are important intermediaries in the activation of the canonical nuclear factor (NF)-κB pathway. More recent data using knockout mice genetically demonstrate that in fact the PKCζ isoform is essential for the adequate activation of this cascade both upstream and downstream the IκB kinase complex. In this review, we summarize the mechanistic details whereby the aPKC pathway regulates important cellular functions and how this is achieved by the ability of these kinases to interact with different protein regulators and adapters, as well as to impinge in NF-κB-independent signaling cascades such as the Janus kinase-1/signal transducer and activator of transcription 6 system, which plays a critical role in T-cell-mediated hepatitis and asthma.