AbstractThe family Picornaviridae comprises a large number of viruses that cause disease in broad spectrum of hosts, which have posed serious public health concerns worldwide and led to significant economic burden. A comprehensive understanding of the virus‐host interactions during picornavirus infections will help to prevent and cure these diseases. Upon picornavirus infection, host pathogen recognition receptors (PRRs) sense viral RNA to activate host innate immune responses. The activated PRRs initiate signal transduction through a series of adaptor proteins, which leads to activation of several kinases and transcription factors, and contributes to the consequent expression of interferons (IFNs), IFN‐inducible antiviral genes, as well as various inflammatory cytokines and chemokines. In contrast, to maintain viral replication and spread, picornaviruses have evolved several elegant strategies to block innate immune signaling and hinder host antiviral response. In this review, we will summarize the recent progress of how the members of family Picornaviridae counteract host immune response through evasion of PRRs detection, blocking activation of adaptor molecules and kinases, disrupting transcription factors, as well as counteraction of antiviral restriction factors. Such knowledge of immune evasion will help us better understand the pathogenesis of picornaviruses, and provide insights into developing antiviral strategies and improvement of vaccines.