The recent entry here on a phenotypic screen got some discussion going in the comments, and I thought I'd bring that out here for more. Some readers objected to the paper being characterized as a phenotypic screen at all, saying that it was just a cell-based screen. That got me to thinking about how I use the term, and to judge from the comments, there are at least two schools of thought on this.
The first says "Phenotypic" to mean something like "Screening for some desired effect in a living system, independent of any defined target". That's where I come from as well, since I've spent so much of my career doing target-based drug discovery. In a target-based program, you have cell assays, too - but they're downstream of the biochemical/pharmacological assay, and are there to answer two key questions: (1) does hitting the desired target do the right things to the cells, and (2) do the compounds break out into new SAR categories in cells that aren't apparent from their activity against the target? That last part can mean that some of the compounds are cytotoxic (while others aren't), or some of them seem to get into cells a lot better than others, and so on. But they're all subordinated to the original target idea, which drives the whole project.
The other definition of phenotypic screen would be something more like: "Screening simultaneously for a broad range of effects in a living system, independent of any defined target". I would call that, personally, a "high-content" screen (or more precisely, a high-content phenotypic screen, but (as mentioned) opinions vary on this. To the people who think this way, that Broad Institute paper I blogged on was merely a cell assay that looked at the most boring endpoint of all (cell death), and hardly lifted its head beyond that. But to a target-based person, everything that involves throwing compounds onto cells, with no defined target in mind, just to see what happens. . .well, that sure isn't target-based drug discovery, so it must be a phenotypic screen. And death is a phenotype, too, you know.
I like both kinds of screening, just for the record. But they're done for different purposes. High-content screening is a great way to harvest a lot of data and generate a lot of hypotheses, but for drug discovery, it can be a bit too much like a firehose water fountain. A more narrowed-down approach (such as "We want to find some compounds that make these kinds of cells perform Action X") is closer to actionable drug discovery efforts.
At any rate, a reader sent along some good high-content-screening work, and I'll blog about that separately. More comparisons will come up then.