Catalytic partial oxidation (CPO) of natural gas into syngas (CO and H-2) at short contact time over precious-metal-structured reactors has received increasing attention in industrial applications. However, only recently, sulfur poisoning of the best-performing and costly rhodium catalysts has been recognized as a serious issue of this technology. This work critically reviews and integrates recent experimental results obtained from our group and others, both at steady state and during transient operation of the CPO reactor, particularly with regard to poisoning/regeneration cycles and low-temperature light-offphase. Furthermore, the origin of sulfur poisoning of Rh active sites during the CPO of methane has been studied via in situ diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, using CO as a probe molecule, and an attempt is made to identify sites responsible for the loss in the catalytic activity by comparing the results with the activity data. The effect of the type of alumina support and the partial substitution of Rh with either Pt or Pd were investigated to enhance the sulfur tolerance of the catalyst.