Cannabidiol (CBD) is an approved antiepileptic with distinct effects on the therapeutically relevant Kv7 channels, it has activating effects on Kv7.2–5 and inhibiting effects on Kv7.1 and the cardiac Kv7.1/KCNE1 channel. Despite a recent CBD bound Kv7.2 structure, the precise mechanism by which it activates Kv7.2–5 channels is unclear. Further, no structures are available for CBD bound to Kv7.1 or indeed any structures at all for Kv7.1/KCNE1, limiting insight into how CBD inhibits these channels. Understanding how CBD has differential effects on the Kv7 ion channels may be key to developing Kv7 subtype selective drugs. We first sought to understand the chemical features of CBD responsible for its effect on Kv7.4, we have recently shown that Kv7.4 is strongly activated by CBD. The binding free energies of chemicals with modified features were calculated using free energy perturbation simulations. We observed that altering the hydroxy groups on the resorcinol ring, reducing the lipophilicity of the aliphatic tail group or changing the orientation/flexibility of the limonene group reduced binding affinity compared to CBD. The modified chemicals were then synthesized and tested through electrophysiologic experiments. Mirroring the simulations, the modified chemicals had a diminished effect on Kv7.4 activation compared to CBD. Switching our focus to Kv7.1 and Kv7.1/KCNE1, we proposed CBD binding modes using docking and molecular dynamics simulations. The binding modes were tested using site directed mutagenesis studies. Our work in progress indicates that CBD binds to the S5 and S6 helices from each subunit in Kv7.1 and from a pair of adjacent subunits in Kv7.1/KCNE1. Collectively, this work furthers our understanding of CBD activity of the Kv7 channels and should aid in drug development initiatives based on the CBD chemical scaffold.