Mentorship relationships impart numerous benefits to early- and middle-career academic physicians—scientists, clinicians, and administrators. Not only influencing mentees’ decisions to enter and remain in academic medicine, these relationships can increase self-confidence and productivity, improve overall career satisfaction, and enhance the mentee’s sense of professional community. Mentee self-awareness and thoughtfully conceived professional development plans are crucial to initiating successful mentoring partnerships. Also essential is the ability to identify and effectively engage mentors who possess talents, expertise, and professional connections likely to benefit the mentee. From the very beginning of the relationship, careful consideration should be given to expectations for the mentorship experience and to structuring mentoring encounters accordingly. Mutually beneficial relationships will be best sustained as the result of thorough preparation for meetings, continuous hard work, and ongoing assessment of outcomes. Mentorships inevitably evolve and/or terminate. Although such terminations may occasionally unfortunately occur as personality conflicts became insurmountable, they most commonly end or fade away in a more developmentally appropriate fashion as goals are met or mentees advance to positions of increased autonomy. Mentorship relationships are dynamic and reciprocal processes, best guided by mentees’ self-determined goals and career visions that evolve and mature through interactive and iterative experiences of mentorship. Academic institutions should provide the vision and resources necessary to build and sustain programs to enhance mentorship, particularly for women and underrepresented minorities, who historically have encountered more difficulty accessing such vital identity-similar career-building relationships.