No, you do not want to rely on mouseclicks for normal skill activations, IMO. For some things, like possibly click healing with a specialized grid setup, maybe. For ground-targeted AoE, obviously it's the only way to do it. For normal hotbar buttons, it works fine when you have the time to make sure you're clicking in the middle of the button (like hearthing, eating/drinking, etc.) but it sucks ass when things are hectic. I've yet to meet anyone that can reliably click tiny buttons in the heat of a PVP battle or when trying to avoid boss AoE or puddles of fire.