Stenotrophomonas maltophilia colonization/infection in patients with cancer has significantly increased over the past 2 decades. Patients with prolonged neutropenia, exposure to broad-spectrum antibiotics, and those requiring mechanical ventilation have higher risk of infection. These micro-organisms are intrinsically resistant to carbapenems, and exposure to these agents has been linked to selection of S. maltophilia. Recently, these infections are being documented in patients without traditional risk factors. The spectrum of infection includes bacteremia, catheter-related infection, pneumonia, complicated biliary and urinary tract infection, and skin and skin-structure infection. Trimethoprim-sulfamethoxazole is the therapeutic agent of choice, but resistance is increasingly being reported. Susceptibility to alternative agents is unpredictable. Combination therapy and alternative routes of drug administration, such as aerosolized aminoglycoside, might be necessary. New insights into the mechanisms of drug resistance might lead to identification of new target sites. Agents that improve outer-membrane permeability and broad-spectrum beta-lactamase inhibitors may favorably impact difficult-to-treat (i.e., multidrug resistant) S. maltophilia infections.