Diagnosis of Crohn's disease (CD) is often challenging and requires the utmost precision and perseverance in defining location, extent, severity and type of disease (inflammatory vs stricturing/penetrating), as well as in excluding septic complications and extraintestinal manifestations. Endoscopy and histology remain, as of today, the best tests for initial diagnosis of CD. Increasingly important roles are played by imaging techniques (small bowel MRI, computed tomographic enterography and intestinal ultrasound) and noninvasive markers of disease such as fecal calprotectin and specific autoantibodies. Here, we will review the main tools presently available to make the initial diagnosis of intestinal and perianal CD, to evaluate the response to treatment and to diagnose disease recurrence after surgery. Finally, we will discuss some of the future diagnostic challenges in CD.