There is no 'sure thing' - just better risk/reward skews.
With properly modeled spreads, you are trading the differential (price differences) between two or more instruments. You hedge out directional risk and the profit/loss comes from divergence or convergence of the spread differential value. It could be cash, futures, stocks, currencies, almost anything. That is relative value, and it's the way many bank desks and hedge funds trade. The vast majority of successful electronic traders I know of here in Chicago are spread traders. For every mad Russian buying 1000 ES futures, there are ten guys who are buying 500 CBOT Two Year Note futures and selling 480 CME Dec 11 Eurodollar futures as a spread. Most spread traders are actually flat at the end of the day.
Stat Arb 'black box' automated trading systems trade markets with very high mean reversion - for example, a basket of closely correlated components with equal long and short components (for example: short V, long X, short Y, long Z) with very, very low volatility; they are literally picking up pennies. By design and methodology, myself and my clients model and trade spreads for statistical characteristics that do not lend themselves particularly well to high frequency automated trading on convergence.