Salmonella enterica infections cause considerable morbidity and mortality worldwide. Antimicrobial therapy may be life-saving for patients with extraintestinal infections with S. enterica serotype Typhi or non-Typhi salmonellae. Because antimicrobial resistance to several classes of traditional first-line drugs has emerged in the past several decades, the quinolone antimicrobial agents, particularly the fluoroquinolones, have become the drugs of choice. Recently, resistance to nalidixic acid has emerged among both Typhi and non-Typhi Salmonella serotypes. Such Salmonella isolates typically also have decreased susceptibility to fluoroquinolones, although minimum inhibitory concentrations of the fluoroquinolones usually are within the susceptible range of the interpretive criteria of the NCCLS. A growing body of clinical and microbiological evidence indicates that such nalidixic acid-resistant S. enterica infections also exhibit a decreased clinical response to fluoroquinolones. In this article, we recommend that laboratories test extraintestinal Salmonella isolates for nalidixic acid resistance, we recommend that short-course fluoroquinolone therapy be avoided for infection with nalidixic acid-resistant extraintestinal salmonellae, and we summarize existing data and data needs that would contribute to reevaluation of the current NCCLS fluoroquinolone breakpoints for salmonellae.