Publisher Summary Picornaviruses are small naked icosahedral viruses with a single-stranded RNA genome of positive polarity. According to current taxonomy, the family includes four genera: Enterouirus (polioviruses, coxsackieviruses, echoviruses, and other enteroviruses), Rhinovirus, Curdiouirus [encephalomyocarditis virus (EMCV), mengovirus, Theiler's murine encephalomyelitis virus (TMEV)], and Aphthouirus [foot-and-mouth disease viruses (FMDV)]. There are also some, as yet, unclassified picornaviruses [e.g., hepatitis A virus (HAW] that should certainly be assessed as a separate genus. Studies on the molecular biology of picornaviruses might be divided into two periods: those before and after the first sequencing of the poliovirus genome. The 5'-untranslated region (5-UTR) of the viral genome was one of the unexpected problems. This segment proved to be immensely long: about 750 nucleotides or ∼10% of the genome length. There were also other unusual features (e.g., multiple AUG triplets preceding the single open reading frame (ORF) that encodes the viral polyprotein). This chapter shows that the picornaviral 5-UTRs are not only involved in such essential events as the synthesis of viral proteins and RNAs that could be expected to some extent, although some of the underlying mechanisms appeared to be quite a surprise, but also may determine diverse biological phenotypes from the plaque size or thermosensitivity of reproduction to attenuation of neurovirulence. Furthermore, a close inspection of the 5-UTR structure unravels certain hidden facets of the evolution of the picornaviral genome. Finally, the conclusions drawn from the experiments with the picornaviral5-UTRs provide important clues for understanding the functional capabilities of the eukaryotic ribosomes.