Over the last decade, dramatic improvements in mass-sensitivity of NMR through low-volume tube probes and capillary probes, coupled with cryogenically cooled radiofrequency (rf) coils and preamplifier components, have provided chemists with new capabilities for exploration of submilligram natural product samples. These innovations led to an approximate 20-fold increase in mass sensitivity compared with conventional NMR instrumentation at the same field. Now, full characterization by 1D and 2D NMR of natural products--some available only in vanishingly small amounts, down to approximately 1 nanomole--can be achieved in reasonable time-frames. In this Highlight, some recent applications of the new NMR methodology to the area of natural products discovery are discussed, along with a perspective of practical limitations and potential future applications in new areas.