ABSTRACT The Belgian National Reference Centre for Salmonella received 16,544 human isolates of Salmonella enterica between January 2009 and December 2013. Although 377 different serotypes were identified, the landscape is dominated by S. enterica serovars Typhimurium (55%) and Enteritidis (19%) in a ratio which is inverse to European Union averages. With outbreaks of Salmonella serotypes Ohio, Stanley, and Paratyphi B variant Java as prime examples, 20 serotypes displayed significant fluctuations in this 5-year period. Typhoid strains account for 1.2% of Belgian salmonellosis cases. Large-scale antibiotic susceptibility analyses ( n = 4,561; panel of 12 antibiotics) showed declining resistance levels in S . Enteritis and Typhimurium isolates for 8 and 3 tested agents, respectively. Despite low overall resistance to ciprofloxacin (4.4%) and cefotaxime (1.6%), we identified clonal lineages of Salmonella serotypes Kentucky and Infantis displaying rising resistance against these clinically important drugs. Quinolone resistance is mainly mediated by serotype-specific mutations in GyrA residues Ser83 and Asp87 (92.2% not wild type), while an additional ParC_Ser80Ile mutation leads to ciprofloxacin resistance in 95.5% S . Kentucky isolates, which exceeds European averages. Plasmid-mediated quinolone resistance (PMQR) alleles qnrA1 ( n = 1), qnrS ( n = 9), qnrD1 ( n = 4), and qnrB ( n = 4) were found in only 3.0% of 533 isolates resistant to nalidixic acid. In cefotaxime-resistant isolates, we identified a broad range of Ambler class A and C β-lactamase genes (e.g., bla SHV-12 , bla TEM-52 , bla CTX-M-14 , and bla CTX-M-15 ) commonly associated with members of the family Enterobacteriaceae . In conclusion, resistance to fluoroquinolones and cefotaxime remains rare in human S. enterica , but clonal resistant serotypes arise, and continued (inter)national surveillance is mandatory to understand the origin and routes of dissemination thereof.