The choice of therapy for patients with advanced colorectal cancer is becoming far more complex than it was a few years ago. First-line therapy of advanced colorectal cancer has rapidly moved from modulation and infusional administration of fluoropyrimidines to more complex regimens with newer chemotherapy drugs (ie, oxaliplatin and irinotecan), and targeted drugs inhibiting angiogenesis (ie, bevacizumab) or the epidermal growth factor receptor (ie, cetuximab and panitumumab). With the availability of new drugs, new regimens, and better management of the disease, median survival has improved from less than 1 year to more than 20 months. Optimal management of patients with advanced colorectal cancer is based not only on the best possible regimen in first-line therapy, but also incorporates several individual parameters, such as resection of metastases in selected cases, optimal use of prognostic and predictive factors, optimal duration of treatment and consideration of chemotherapy-free intervals, and choice of second- and third-line treatment. This review summarizes the state-of-the-art in the management of patients with advanced colorectal cancer, discussing topical issues toward the individualization of treatment strategy.