In eukaryotes, the genome is organized into a complex nucleoprotein structure called chromatin. Despite the simplicity of its monomer, DNA and two copies of four histones, the existence of histone variants opens possibilities of multiple chromatin landscapes and fine-tune regulation of molecular mechanisms for the regulation of gene expression and maintenance of genome stability. However, any defects in these combinations may contribute to disease development and/or progression. Here, I review human histone variants and their chaperones, and discuss how they contribute to pathological conditions.