Cytokines are well known for their pleiotropism, affecting a large number of cellular responses, including proliferation, survival, functional maturation, and immunomodulation. It is, therefore, not surprising that both the deregulated expression of cytokines and the subsequent activation of their downstream signaling pathways is a common feature of many cancers, as well as chronic inflammatory, autoimmune, metabolic, and cardiovascular diseases. In this regard, activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is the predominant intracellular signaling event triggered by cytokines, with STAT1 and STAT3 having the greatest diversity of biological functions among the 7 known members of the STAT family of latent transcription factors. Notably, over recent years, it has emerged that STAT1 and STAT3 are employed by various cytokines to manipulate the signal output of heterologous receptors of the innate immune system, namely pattern recognition receptors (PRRs), with both immune and nonimmune (eg, oncogenic, metabolic) cellular processes being affected. This review highlights these pivotal advancements in our understanding of how a cross talk between cytokine and PRR signaling networks can impact on a variety of cellular responses during disease pathogenesis, and the potential therapeutic implications of targeting these networks.