DNA in eukaryotic cells is compacted into chromatin, a regular repeated structure in which the nucleosome represents the basic unit. The nucleosome not only serves to compact the genetic material but also provides information that affects nuclear functions including DNA replication, repair and transcription. This information is conveyed through numerous combinations of histone post-translational modifications (PTMs) and histone variants. A recent challenge has been to understand how and when these combinations of PTMs are imposed and to what extent they are determined by the choice of a specific histone variant. Here we focus on histone H3 variants and the PTMs that they carry before and after their assembly into chromatin. We review and discuss recent knowledge about how the choice and initial modifications of a specific variant might affect PTM states and eventually the final epigenetic state of a chromosomal domain.