This year (2013) marks the 20th anniversary of identification of the causal genetic mutation for Huntington's disease (HD), a landmark discovery that heralded study of the biological underpinnings of this most common dominantly inherited neurodegenerative disorder. Among the variety of model organisms used to study HD pathogenesis, the mouse model is by far the most commonly used mammalian genetic model. Much of our current knowledge regarding mutant huntingtin (mHtt)-induced disease pathogenesis in mammalian models has been obtained by studying transgenic mouse models expressing mHtt N-terminal fragments, full-length murine or human mHtt. In this review, we focus on recent progress in using novel HD mouse models with targeted mHtt expression in specific brain cell types. These models help to address the role of distinct neuronal and non-neuronal cell types in eliciting cell-autonomous or non-cell-autonomous disease processes in HD. We also describe several mHtt transgenic mouse models with targeted mutations in Htt cis-domains to address specific pathogenic hypotheses, ranging from mHtt proteolysis to post-translational modifications. These novel mouse genetic studies, through direct manipulations of the causal HD gene, utilize a reductionist approach to systematically unravel the cellular and molecular pathways that are targeted by mHtt in disease pathogenesis, and to potentially identify novel targets for therapy.