Horizontal gene transfer of mobile genetic elements (MGEs) accounts for the mosaic genome of Clostridium difficile, leading to acquisition of new phenotypes, including drug resistance and reconstruction of the genomes. MGEs were analyzed according to the whole-genome sequences of 37 C. difficile isolates with a variety of sequence types (STs) within clade 4 from China. Great diversity was found in each transposon even within isolates with the same ST. Two novel transposons were identified in isolates ZR9 and ZR18, of which approximately one third to half of the genes showed heterogenous origins compared with the usual intestinal bacterial genes. Most importantly, catD, known to be harbored by Tn4453a/b, was replaced by aac(6′) aph(2′′) in isolates 2, 7, and 28. This phenomenon illustrated the frequent occurrence of gene exchanges between C. difficile and other enterobacteria with individual heterogeneity. Numerous prophages and CRISPR arrays were identified in C. difficile isolates of clade 4. Approximately 20% of spacers were located in prophage-carried CRISPR arrays, providing a new method for typing and tracing the origins of closely related isolates, as well as in-depth studies of the mechanism underlying genome remodeling. The rates of drug resistance were obviously higher than those reported previously around the world, although all isolates retained high sensitivity to vancomycin and metronidazole. The increasing number of C. difficile isolates resistant to all antibiotics tested here suggests the ease with which resistance is acquired in vivo. This study gives insights into the genetic mechanism of microevolution within clade 4.