Endophytic actinomycetes associated with plant roots are a relatively untapped source of potential new bioactive compounds. This is becoming increasingly important, as the returns from discovery research on soil-dwelling microbes, have been continuously diminishing. We have isolated more than 1000 strains of actinomycetes from plant roots in our search for novel bioactive compounds, identified and assayed their bioactive metabolites, as well as investigated their biosynthetic genes for generating secondary metabolites. This has resulted in the discovery of several interesting compounds. Creation of plant root clone libraries enabled us to confirm that we had, indeed, isolated endophytes. In this paper, we introduce our approach to this promising line of research, incorporating data from other publications, and illustrate the potential that endophytic actinomycetes offer as a new source of novel lead compounds.