Worldwide, colorectal cancer (CRC) is responsible for over 600,000 deaths annually and remains a significant public health concern. Because of therapeutic advancements over the past two decades, patients with metastatic CRC are living longer with an improved quality of life. This review will highlight recent trial evidence that improves outcomes for patients with metastatic disease. Topics will include the optimal use of first-line combination chemotherapy, bevacizumab in patients with advanced age or comorbidities, maintenance chemotherapy, first-line use of anti-EGFR therapies, first-line cetuximab versus bevacizumab, anti-angiogenic therapies past progression, and management of treatment-refractory disease. Clinical trial evidence will be presented, along with guidance on how to integrate recent evidence into clinical practice. Finally, this review will examine innovative drug development strategies, and will discuss potentially actionable targets identified by molecular testing.