Marked clinical and biologic heterogeneity exists in multiple myeloma (MM). Over the years, many prognostic factors have been identified and several prognostic systems have been proposed. The integration of data from international groups including patients treated with common modalities such as chemotherapy and high-dose therapy culminated in the International Staging System. Recently, genetic information has also been shown to include powerful prognostic factors across different treatment modalities. These advances have facilitated categorization of patients into different risk groups, particularly a subset of patients at high risk with short survival times after current standard therapy. The expanding armamentarium of effective treatments in MM also means that it is now possible to select treatments for patients based on their risk categories. This review will summarize the important prognostic factors identified to date, how they can be used to identify patients at high risk, and their clinical utility in relation to treatment optimization at diagnosis.