The Picornaviridae family comprises a heterogeneous group of non-enveloped viruses with genome consisting of a single positive-sense RNA strand. Infections with picornaviruses are very common in humans, producing a spectrum of clinical outcomes, ranging from asymptomatic infection and mild respiratory illness, to meningitis, myocarditis, pericarditis, and enterovirus-induced septic syndrome. Most picornaviruses seem to develop resistance quite effectively against almost any chemotherapeutic agent that modern science has developed, presenting a truly formidable challenge to modern healthcare. For some time, it has been hoped that synthetic agents mimicking the naturally occurring sphingosine-like molecule occupying the hydrophobic pocket in the viral capsid may be useful as antiviral agents, but it has been repeatedly demonstrated that resistance to the pocket-binding antivirals develops quite rapidly and that viral strains dependent on the chemotherapeutic may emerge. Several pocket-binding pyrazole drugs have entered clinical trials so far, but as of now, none of these have been licensed by the FDA, despite the extensive clinical trials. Apparently, the search for means of prevention of infection with rhino- and enteroviruses or an etiotropic cure for the conditions related to infections with picornaviruses is still ongoing.