Spectroscopic systems and methods are disclosed for determining levels of at least one analyte in blood undergoing hemodialysis. In one aspect, the invention employs Raman spectroscopy to monitor and/or control hemodialysis. In one embodiment, the system uses a laser light directed to circulating blood from a patient undergoing dialysis to make Raman spectral measurements. For example, the laser light can be directed into a segment of the dialysis tubing. The system can utilize unique Raman spectroscopic signature of one or more analytes, e.g., urea, to identify and quantify such analytes against a whole blood background. Based on the spectral response, the concentration of the analytes can be monitored and/or used to control hemodialysis.