Human centromeres are genomic regions that act as sites of kinetochore assembly to ensure proper chromosome segregation during mitosis and meiosis. Although the biological importance of centromeres in genome stability, and ultimately, cell viability are well understood, the complete sequence content and organization in these multi-megabase-sized regions remains unknown. The lack of a high-resolution reference assembly inhibits standard bioinformatics protocols, and as a result, sequence-based studies involving human centromeres lag far behind the advances made for the non-repetitive sequences in the human genome. In this chapter, I introduce what is known about the genomic organization in the highly repetitive regions spanning human centromeres, and discuss the challenges these sequences pose for assembly, alignment, and data interpretation. Overcoming these obstacles is expected to issue a new era for centromere genomics, which will offer new discoveries in basic cell biology and human biomedical research.