The ability to identify classically secreted proteins is an important component of targeted therapeutic studies and the discovery of circulating biomarkers. Here, we review some of the most recent programs available for the in silico prediction of secretory proteins, the performance of which is benchmarked with an independent set of annotated human proteins. The description of these programs and the results of this benchmarking provide insights into the most recently developed prediction programs, which will enable investigators to make more informed decisions about which program best addresses their research needs.