Since, generally, an HSA is triple-tax-advantaged, if you already have a ROTH and a 401k, I'd put my most high-risk, high-reward investments in the HSA. Then, the next tier I'd put in a Roth (medium-to-high risk, dividends, long shots, etc), and my most basic investments (bonds, TIPS, boring index funds, etc) in the 401k.
Unless you live in California or New Jersey, in which case your HSA transactions are taxable and require an adjustment to strategy... you don't want to be jumping in and out of speculative investments and triggering capital gains taxes every time, which may require you to take money out of the HSA just to pay the income taxes on it. Even dealing with dividends might suck.