Streptococcus suis serotype 2 (S. suis S2) is able to cause human infections ranging from superficial wounded skin infections to severe invasive infections such as meningitis and streptococcal toxic shock-like syndrome. During its infection cycle, S. suis S2 must acclimatize itself to temperature shift. Herein, a whole-genome DNA microarray was used to investigate the global transcriptional regulation of an invasive strain of S. suis S2 grown to late-exponential phase at 29°C or 40°C relative to 37°C. The differentially regulated genes that were detected included those encoding virulence factors, antigenic proteins, ATP-binding-cassette transporters, and proteins of unknown functions. Our data provided a global profile of gene transcription induced by temperature alteration and shed light on some unforeseen lines for further pathogenesis investigation.