Cellulose nanocrystals (CNCs) are naturally-sourced nanoparticles that can be used to modify polymers and provide exceptional mechanical properties to nanocomposite materials. In this study, CNCs were incorporated into water-based pressure sensitive adhesives (PSAs) via in situ semi-batch emulsion polymerization to improve PSA properties. A sequential design approach was used to improve CNC/ poly(n-butyl acrylate/vinyl acetate) nanocomposite PSAs. In the first part of the design, the effects of acrylic acid (AA) and anionic surfactant sodium dodecyl sulfate (SDS) were examined in the presence of 0.5 wt% CNCs (based on polymer mass). While the SDS was crucial to maintaining latex stability, its excessive addition led to a decrease in PSA performance, namely tack and peel strength. The AA comonomer was pivotal in improving the shear strength of the PSAs, especially in the presence of CNCs. In all cases, the addition of CNCs led to improved PSA shear strength. In the second part of the design, the addition of 1-dodecanethiol (NDM) as a chain transfer agent (CTA) with CNC levels up to 1 wt% led to an improvement in tack and peel strength but at the cost of diminishing the shear strength. Generally, the addition of CNCs improved PSA performance. Thus, to maximize the impact of CNCs on PSA properties, a careful balance of SDS (for latex stability), AA (to improve shear strength) and NDM (to improve tack and peel strength) are needed.