Probiotics are investigated as single-strain and multistrain products. In the market, however, there is an increasing tendency to work with multistrain probiotics, in particular, products with a high number of different strains. There are some thoughts behind this: more strains imply more chances of success; it can mean a broader spectrum of efficacy, and there is often the hope that there are at least additive and, potentially, even synergistic effects. The present review did not find convincing evidence that these assumptions are valid. There is, however, also no strong evidence that the assumptions are incorrect and/or that there is antagonistic activity between strains in a combination. We suggest that, to answer these questions, structured research is conducted. Starting with a systematic review of meta-analyses that have compared single-strain and multistrain probiotic efficacy, dedicated human studies need to be performed, comparing single-strain and multistrain probiotics to each other and placebo. In vitro and animal studies can provide indications and may help understand mechanisms. For human, animal, and in vitro studies, it is recommended to work with the simple setup of 2 single strains, a 2-strain combination, and placebo. It is also important in such research to take into consideration the doses, as a combination product will have a higher total dose.