This chapter discusses procedures that can be used when the classical approach for establishing the cause of a virus-like disease is neither successful nor appropriate. It describes an overall plan for gaining sufficient information on nucleic acids found only in diseased plants, provides an unambiguous preliminary classification by type, size, and circularity. The path towards determining the cause of plant diseases is well trodden, and virologists are well aware of the sequence of events which commonly leads them to being asked to study a disease. Ability to spread is one of the main characteristics of infectious diseases, and mapping of disease distribution and movement may be used to provide evidence of transmission in the field. Some plants, including many species of palm, cannot be cloned vegetatively to allow an increase in the amount of diseased material. Perennial plants which are not able to be reproduced by vegetative cloning are good candidates for harboring pathogens causing diseases of unknown etiology.