Association of the human tumor suppressor p53 with many human cancers makes it a valuable therapeutic target. Stress-induced molecular interactions of p53 with other effector proteins are immensely intertwined with regulation of its functions in orchestrating a wide array of cellular responses, thereby defying analysis of the underlying molecular mechanisms with conventional molecular and cellular biology methods. Recent discoveries of small molecules that can selectively modulate the molecular interactions of p53 offer promising opportunities to address the challenge of dissecting these complex mechanisms and increase the hope for pharmacological control of p53 for clinical benefits of cancer patients.